chr13-51946335-C-T

Position:

• chr13-51946335-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000053.4(ATP7B):​c.3009G>A​(p.Ala1003Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,607,684 control chromosomes in the GnomAD database, including 3,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (217 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2819 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -4.22

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 13-51946335-C-T is Benign according to our data. Variant chr13-51946335-C-T is described in ClinVar as [Benign]. Clinvar id is 35714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946335-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3009G>A	p.Ala1003Ala	synonymous_variant	13/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3009G>A	p.Ala1003Ala	synonymous_variant	13/21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.0427 AC: 6500 AN: 152230 Hom.: 213 Cov.: 33

Gnomad AFR AF: 0.00916

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0764

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0549 AC: 13079 AN: 238048 Hom.: 477 AF XY: 0.0609 AC XY: 7879 AN XY: 129412

Gnomad AFR exome AF: 0.00674

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.00965

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0763

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0569

GnomAD4 exome AF: 0.0580 AC: 84356 AN: 1455336 Hom.: 2819 Cov.: 32 AF XY: 0.0601 AC XY: 43504 AN XY: 723460

Gnomad4 AFR exome AF: 0.00701

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0727

Gnomad4 EAS exome AF: 0.00936

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0765

Gnomad4 NFE exome AF: 0.0570

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome AF: 0.0427 AC: 6503 AN: 152348 Hom.: 217 Cov.: 33 AF XY: 0.0441 AC XY: 3287 AN XY: 74494

Gnomad4 AFR AF: 0.00911

Gnomad4 AMR AF: 0.0315

Gnomad4 ASJ AF: 0.0746

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0764

Gnomad4 NFE AF: 0.0564

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0458 Hom.: 87

Bravo AF: 0.0356

Asia WGS AF: 0.0660 AC: 228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Wilson disease Benign:7

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1801247; hg19: chr13-52520471; COSMIC: COSV54438365;