rs60986317

Positions:

chr13-51934853-G-A

Variant summary

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

The NM_000053.4(ATP7B):c.4301C>T(p.Thr1434Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,208 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1434T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:13

Conservation

PhyloP100: 1.47

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:

ATP7B (HGNC:):

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=0.008024335).

BP6

Variant 13-51934853-G-A is Benign according to our data. Variant chr13-51934853-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=7, Benign=1}. Variant chr13-51934853-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.4301C>T	p.Thr1434Met	missense_variant	21/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.4301C>T	p.Thr1434Met	missense_variant	21/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

408

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00197

AC:

491

AN:

249530

Hom.:

AF XY:

0.00179

AC XY:

243

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00528

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.00904

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00119

AC:

1745

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

831

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.00934

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.000848

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00270

AC:

411

AN:

152368

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

213

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00527

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.000867

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00303

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00504

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.00190

AC:

230

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:5Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000053.3(ATP7B):c.4301C>T(T1434M) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. T1434M has been observed in cases with relevant disease (PMID 29482223, 18483695, 10544227, 22484412, 32154060). Functional assessments of this variant are available in the literature (PMID: 14962673, 21454443). T1434M has been observed in population frequency databases (gnomAD: ASJ 0.91%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.4301C>T(T1434M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 26, 2018	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PM5. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2018	- -

not provided

Uncertain:2Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATP7B: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 29, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2022	Variant summary: ATP7B c.4301C>T (p.Thr1434Met) results in a non-conservative amino acid change in 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 0.002 in 249530 control chromosomes, including 1 homozygote, in the gnomAD database (v 2.1 exomes dataset). The variant was observed predominantly within the African or African-American subpopulation at a frequency of 0.0053. This frequency is close to the maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0053 vs. 0.0054), suggesting that the variant might be benign. The variant, c.4301C>T, has been reported in the literature in individuals affected with Wilson Disease (Loudianos_1999, Abdelghaffar_2008, Lepori_2012) and other disease phenotypes (e.g. Vasta_2012, Demily_2017, Coutelier_2018). However, co-occurrences with other pathogenic variant have been reported (ATP7B homozygous c.3809A>G (p.Asn1270Ser); Abdelghaffar_2008) that could explain the patient's phenotype, thus providing supporting evidence for a benign role. A recent study found the variant in French residents, who were treated with indications other than Wilson Disease (WD), hepatic or neurological diseases, at a frequency of 0.00645 (i.e. 9/1394 alleles), whereas the variant was not found in their WD database, which included 496 index cases. Publications also reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant (Braiterman_2011, Hsi_2003). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2019	The p.Thr1323Met variant in ATP7B (also described as p.Thr1434Met) has been reported in at least 1 heterozygous individual and 1 homozygous individual with Wilson disease; however the homozygous individual was also homozygous for a known pathogenic variant in ATP7B (Loudianos 1999, Abdel Ghaffar 2008, Abdel Ghaffar 2011). This variant has also been reported in ClinVar (Variation ID#35730). This variant was also reported in 4 heterozygous individuals with other neuropsychiatric diseases and were not observed to have typical Wilson disease features (Bell 2011 and Demily 2017). In vitro functional studies in yeast do not suggest copper transport or complementation are impaired (Hsi 2004); however, these types of assays may not accurately represent biological function. This variant has been identified in 0.877% (89/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs60986317). In summary, due to its population frequency and functional data and findings with other pathogenic variants, the p.Thr1323Met variant is classified as likely benign. ACMG/AMP Criteria applied: BS3, BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;T;.;.;.;.;.

Eigen

Benign

0.097

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.0080

T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;N;N;N;N;.;N

REVEL

Benign

0.20

Sift

Benign

0.093

T;T;T;T;T;.;T

Sift4G

Benign

0.24

T;T;T;T;T;T;T

Polyphen

0.89

P;D;D;P;D;D;D

Vest4

0.19

MVP

0.84

MPC

0.30

ClinPred

0.018

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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