rs61733679

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000053.4(ATP7B):c.3369G>A(p.Pro1123Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

ATP7B
NM_000053.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -0.534

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 13-51942429-C-T is Benign according to our data. Variant chr13-51942429-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92388.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=3}. Variant chr13-51942429-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.534 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00334 (509/152282) while in subpopulation AFR AF= 0.0117 (487/41558). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.3369G>A	p.Pro1123Pro	synonymous_variant	Exon 15 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.3369G>A	p.Pro1123Pro	synonymous_variant	Exon 15 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000850

AC:

212

AN:

249552

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000343

AC:

501

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0108

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.000993

GnomAD4 genome

AF:

0.00334

AC:

509

AN:

152282

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

252

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.00364

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:1Benign:6

Oct 23, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:2

Jun 15, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATP7B c.3369G>A (p.Pro1123Pro) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 135/120756 (1/894), predominantly in the African cohort, 118/9800 (1/83), which exceeds the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/1851. Therefore, suggesting the variant of interest is a common polymorphism found in population(s) of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as likely benign until additional information becomes available. -

Jun 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 10, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.1

DANN

Benign

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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