rs72552259

chr13-51960274-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:2
• Conservation: PhyloP100: 2.43

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000053.4
• 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: {Uncertain_significance=15, Likely_benign=2}. Variant chr13-51960274-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.1995G>A	p.Met665Ile	missense_variant	7/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.1995G>A	p.Met665Ile	missense_variant	7/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152182 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.00169 AC XY: 228 AN XY: 135198

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.: 10 Cov.: 31 AF XY: 0.00221 AC XY: 1605 AN XY: 727102

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.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74458

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.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.00263 AC: 22

ExAC AF: 0.00132 AC: 160

EpiCase AF: 0.00213

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:11 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Oct 22, 2021	- -
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	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	Revvity Omics, Revvity	May 06, 2023	- -
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. -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	Observed with a pathogenic variant on the opposite allele (in trans) in a patient with Wilson disease in the published literature, however the patient had an atypical phenotype and a variant in the MTIX gene that could be responsible for the clinical presentation (Van Biervliet et al., 2015); Observed with a second variant in published literature in multiple patients diagnosed with WD, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ferenci et al., 2014; Nilles et al., 2023); 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, 23518715, 32118851, 32154060, 32248359, 30275481, 33640437, 25825851, 32043565, 30097039, 36573661, 34620762, 24517292) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 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	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T;.;.;.
Eigen	Benign	-0.0078
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs72552259; hg19: chr13-52534410;