rs72552259

Positions:

chr13-51960274-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000053.4(ATP7B):c.1995G>A(p.Met665Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,894 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M665V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:2

Conservation

PhyloP100: 2.43

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011927754).

BP6

Variant 13-51960274-C-T is Benign according to our data. Variant chr13-51960274-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=16}. Variant chr13-51960274-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.1995G>A	p.Met665Ile	missense_variant	7/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1995G>A	p.Met665Ile	missense_variant	7/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00150

AC:

374

AN:

249208

Hom.:

AF XY:

0.00169

AC XY:

228

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00174

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00211

AC:

3090

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1605

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00628

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00229

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152300

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00237

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000248

AC:

ESP6500EA

AF:

0.00263

AC:

ExAC

AF:

0.00132

AC:

160

EpiCase

AF:

0.00213

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:12Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Oct 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense variant c.580G>C(p.Ala194Pro) in ETHE1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.580G>C(p.Ala194Pro) variant is absent in gnomAD Exomes. The amino acid Ala at position 194 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen-probably damaging, SIFT-damagind and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid p.Ala194Pro in ETHE1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 12, 2017	The ATP7B c.1995G>A (p.Met665Ile) missense variant has been reported in at least six studies in which it is found in a compound heterozygous state in three individuals, including two individuals with a diagnosis of Wilson disease and one young child who was asymptomatic, in one individual with Wilson disease where zygosity is not stated and in at least two additional patient alleles. The variant was also found in a heterozygous state in five unaffected individuals, and in six of 2100 control chromosomes (Loudianos et al. 1998; Lepori et al. 2012; Bost et al. 2012; Coffey et al. 2013; Van Biervliet et al. 2015; Dopazo et al. 2016). The p.Met665Ile variant is reported at a frequency of 0.006403 in the Ashkenazi Jewish population of the Genome Aggregation Database; this database also reports two individuals who are homozygous for this variant. At this time, it is unknown if these individuals can be explained by reduced penetrance, mild or late onset of symptoms, or if this is evidence supporting a benign classification of the p.Met665Ile variant. Based on the available evidence, the p.Met665Ile variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	The ATP7B c.1995G>A, p.Met665Ile variant (rs72552259) is reported in the literature in multiple individuals affected with Wilson disease, including in at least two individual with a pathogenic variant detected in trans (Bost 2012, Coffey 2013, Ferenci 2014, Lepori 2012, Loudianos 1998, Van Biervliet 2015, Weiss 2010). This variant is reported in ClinVar (Variation ID: 157933), and is found in the general population with an overall allele frequency of 0.15% (408/280,594 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 665 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.655). Due to limited information, the clinical significance of the p.Met665Ile variant is uncertain at this time. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013; 136(Pt 5):1476-87. Ferenci P et al. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci. 2014 May;1315:1-5. Lepori MB et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 Aug;26(4):147-50. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998; 12(2):89-94. Van Biervliet S et al. Clinical zinc deficiency as early presentation of Wilson disease. J Pediatr Gastroenterol Nutr. 2015;60(4):457-9. Weiss KH et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40. -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20517649, 22677543, 9671269, 22692182, 26764160, 10447265, 22484412, 32118851, 32154060, 32248359, 30275481, 33640437, 32043565, 30097039, 34405919, 30476936, 24517292, 23518715, 25825851, 34620762, 37937776, 36573661) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP7B: PM5, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 17, 2023

Variant summary: ATP7B c.1995G>A (p.Met665Ile) results in a conservative amino acid change located in the TMA domain (Wallace_2020) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251308 control chromosomes (including one homozygote), predominantly at a frequency of 0.0067 within the Ashkenazi Jewish subpopulation in the gnomAD database (v2, Exomes cohort). The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), suggesting that the variant may be a benign polymorphism in populations of Ashkenazi Jewish origin. However, higher frequencies of pathogenic variants as well as later onset of disease and milder disease phenotypes have been noted in the literature in the Ashkenazi Jewish subpopulation (PMIDs: 32248359, 2382969, 13797909). c.1995G>A, has been reported in the literature in multiple compound heterozygous individuals affected with Wilson Disease (WD) with pathogenic variants in trans (e.g. Coffey_2013, VanBiervliet_2015, Ferenci_2019, Tampaki_2020, Collins_2021). However, for many WD individuals with the variant in the literature, a second mutation is not provided (e.g., Bost_2012, Lepori_2012, Loudianos_1998, Penon-Portmann_2020, Tampaki_2020). Other missense changes at the same codon, p.Met665Val and p.Met665Arg, have been classified as variants of uncertain significance by our laboratory. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 14 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=12), likely benign (n=1) and likely pathogenic (n=1). In light of available patient data, it is not certain whether this variant represents a relatively mild mutation resulting in a slight aberration in Cu metabolism leading to an atypical presentation or later onset of WD. The presence of three homozygotes in the gnomAD database (v2 & v3 combined) further support that this variant may result in reduced penetrance or a later onset of subclinical cases. Additional information, such as a phenotypical and biochemical data, preferably from a homozygous individual, is needed to ascertain this variant with confidence. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The c.1995G>A (p.M665I) alteration is located in exon 7 (coding exon 7) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 1995, causing the methionine (M) at amino acid position 665 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;T;.;.;.

Eigen

Benign

-0.0078

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Benign

0.082

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.9

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

N;N;D;.;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.021

D;T;D;.;D

Sift4G

Benign

0.062

T;T;T;T;T

Polyphen

0.17

B;B;B;B;B

Vest4

0.39

MutPred

0.81

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.93

MPC

0.066

ClinPred

0.016

GERP RS

4.5

Varity_R

0.38

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over