rs2282057

Positions:

• chr13-51937470-G-A

Variant summary

Our verdict is Benign. Variant got -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 donor 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. 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_donor_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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3903+6C>T		splice_donor_region_variant, intron_variant		ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3903+6C>T		splice_donor_region_variant, intron_variant		1	NM_000053.4	ENSP00000242839	P1

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

GnomAD3 exomes AF: 0.538 AC: 134118 AN: 249346 Hom.: 36550 AF XY: 0.542 AC XY: 73313 AN XY: 135302

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 SAS exome AF: 0.510

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

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.568

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.509

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.561

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

Gnomad4 AFR AF: 0.483

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.565

Alfa AF: 0.556 Hom.: 14439

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

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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:7

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely 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	-0.82
CADD	Benign	0.79
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

LitVar

Other links and lift over

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