chr13-51937470-G-A

Variant names:

• chr13-51937470-G-A
• rs2282057
• NM_000053.4:c.3903+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.3903+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,818 control chromosomes in the GnomAD database, including 256,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22105 hom., cov: 33)
  • Exomes 𝑓: 0.56 (234650 hom.)
• Consequence: ATP7B NM_000053.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003007
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 0.0100

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-51937470-G-A is Benign according to our data. Variant chr13-51937470-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51937470-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3903+6C>T		splice_region_variant, intron_variant	Intron 18 of 20	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3903+6C>T		splice_region_variant, intron_variant	Intron 18 of 20	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81559 AN: 151998 Hom.: 22099 Cov.: 33

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.563

GnomAD2 exomes AF: 0.538 AC: 134118 AN: 249346 AF XY: 0.542

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.565 AC: 825145 AN: 1461702 Hom.: 234650 Cov.: 73 AF XY: 0.564 AC XY: 409871 AN XY: 727162

African (AFR) AF: 0.486 AC: 16257 AN: 33480

American (AMR) AF: 0.492 AC: 22022 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 14853 AN: 26136

East Asian (EAS) AF: 0.402 AC: 15977 AN: 39700

South Asian (SAS) AF: 0.509 AC: 43879 AN: 86258

European-Finnish (FIN) AF: 0.604 AC: 32192 AN: 53286

Middle Eastern (MID) AF: 0.624 AC: 3601 AN: 5768

European-Non Finnish (NFE) AF: 0.578 AC: 642515 AN: 1111962

Other (OTH) AF: 0.561 AC: 33849 AN: 60390

GnomAD4 genome AF: 0.536 AC: 81607 AN: 152116 Hom.: 22105 Cov.: 33 AF XY: 0.536 AC XY: 39854 AN XY: 74376

African (AFR) AF: 0.483 AC: 20038 AN: 41490

American (AMR) AF: 0.504 AC: 7706 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1955 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2104 AN: 5154

South Asian (SAS) AF: 0.514 AC: 2478 AN: 4822

European-Finnish (FIN) AF: 0.600 AC: 6360 AN: 10598

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39217 AN: 67972

Other (OTH) AF: 0.565 AC: 1194 AN: 2114

Alfa AF: 0.550 Hom.: 19589

Bravo AF: 0.528

Asia WGS AF: 0.503 AC: 1744 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.582

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Benign:8

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 18, 2011

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:7

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 61.035% in ExAC) based on the frequency threshold of 2.434% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.8 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.61
PhyloP100		0.010
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0
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

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Other links and lift over

dbSNP: rs2282057; hg19: chr13-52511606; COSMIC: COSV54440224; COSMIC: COSV54440224;