13-52011412-G-T

Variant names:

• chr13-52011412-G-T
• rs2277448
• NM_000053.4:c.-75C>A

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.-75C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,603,372 control chromosomes in the GnomAD database, including 365,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27561 hom., cov: 34)
  • Exomes 𝑓: 0.68 (337517 hom.)
• Consequence: ATP7B NM_000053.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.36
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-52011412-G-T is Benign according to our data. Variant chr13-52011412-G-T is described in ClinVar as Benign. ClinVar VariationId is 312405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.-75C>A		5_prime_UTR_variant	Exon 1 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.-75C>A		5_prime_UTR_variant	Exon 1 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87665 AN: 151958 Hom.: 27555 Cov.: 34

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.638

GnomAD4 exome AF: 0.678 AC: 983477 AN: 1451296 Hom.: 337517 Cov.: 28 AF XY: 0.675 AC XY: 487811 AN XY: 722498

African (AFR) AF: 0.289 AC: 9598 AN: 33154

American (AMR) AF: 0.660 AC: 29266 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 16525 AN: 26052

East Asian (EAS) AF: 0.564 AC: 22292 AN: 39552

South Asian (SAS) AF: 0.545 AC: 46793 AN: 85906

European-Finnish (FIN) AF: 0.700 AC: 37118 AN: 53006

Middle Eastern (MID) AF: 0.697 AC: 4009 AN: 5752

European-Non Finnish (NFE) AF: 0.705 AC: 778083 AN: 1103492

Other (OTH) AF: 0.663 AC: 39793 AN: 60056

GnomAD4 genome AF: 0.577 AC: 87687 AN: 152076 Hom.: 27561 Cov.: 34 AF XY: 0.578 AC XY: 42971 AN XY: 74336

African (AFR) AF: 0.304 AC: 12609 AN: 41478

American (AMR) AF: 0.646 AC: 9893 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2228 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3061 AN: 5144

South Asian (SAS) AF: 0.539 AC: 2602 AN: 4826

European-Finnish (FIN) AF: 0.705 AC: 7455 AN: 10570

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47788 AN: 67964

Other (OTH) AF: 0.640 AC: 1352 AN: 2114

Alfa AF: 0.605 Hom.: 15171

Bravo AF: 0.564

Asia WGS AF: 0.560 AC: 1945 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Benign:5

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital disorder of glycosylation Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.1
DANN	Benign	0.47
PhyloP100		-1.4
PromoterAI		-0.0028	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2277448; hg19: chr13-52585548; COSMIC: COSV54445614; COSMIC: COSV54445614;