rs61733679

Positions:

• chr13-51942429-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000053.4(ATP7B):​c.3369G>A​(p.Pro1123=) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.534

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 -10 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=5, Benign=3, Uncertain_significance=1}. Variant chr13-51942429-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.534 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3369G>A	p.Pro1123=	synonymous_variant	15/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3369G>A	p.Pro1123=	synonymous_variant	15/21	1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152164 Hom.: 2 Cov.: 32

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.: 0 AF XY: 0.000583 AC XY: 79 AN XY: 135400

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.: 1 Cov.: 32 AF XY: 0.000290 AC XY: 211 AN XY: 727244

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.: 2 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74448

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.: 2

Bravo AF: 0.00364

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	- -
Uncertain significance, 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, 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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2016	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 26, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

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

Other links and lift over

dbSNP: rs61733679; hg19: chr13-52516565;