rs7325983

Positions:

• chr13-51946491-C-G

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.2866-13G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 1,613,784 control chromosomes in the GnomAD database, including 4,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1277 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2862 hom.)
• Consequence: ATP7B NM_000053.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.286

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=-0.81).
• BP6: Variant 13-51946491-C-G is Benign according to our data. Variant chr13-51946491-C-G is described in ClinVar as [Benign]. Clinvar id is 35709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946491-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.2866-13G>C		splice_polypyrimidine_tract_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.2866-13G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15560 AN: 152168 Hom.: 1279 Cov.: 33

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.0394

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.0480

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0852

GnomAD3 exomes AF: 0.0693 AC: 17245 AN: 248860 Hom.: 894 AF XY: 0.0647 AC XY: 8734 AN XY: 135060

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0920

Gnomad EAS exome AF: 0.0463

Gnomad SAS exome AF: 0.0577

Gnomad FIN exome AF: 0.0451

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0700

GnomAD4 exome AF: 0.0527 AC: 77064 AN: 1461498 Hom.: 2862 Cov.: 33 AF XY: 0.0522 AC XY: 37969 AN XY: 727018

Gnomad4 AFR exome AF: 0.241

Gnomad4 AMR exome AF: 0.0993

Gnomad4 ASJ exome AF: 0.0925

Gnomad4 EAS exome AF: 0.0366

Gnomad4 SAS exome AF: 0.0573

Gnomad4 FIN exome AF: 0.0497

Gnomad4 NFE exome AF: 0.0437

Gnomad4 OTH exome AF: 0.0649

GnomAD4 genome AF: 0.102 AC: 15589 AN: 152286 Hom.: 1277 Cov.: 33 AF XY: 0.100 AC XY: 7473 AN XY: 74452

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.0883

Gnomad4 ASJ AF: 0.0896

Gnomad4 EAS AF: 0.0397

Gnomad4 SAS AF: 0.0615

Gnomad4 FIN AF: 0.0480

Gnomad4 NFE AF: 0.0453

Gnomad4 OTH AF: 0.0844

Alfa AF: 0.0730 Hom.: 113

Bravo AF: 0.111

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 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. -

Wilson disease Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 14, 2022	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -

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	-0.81
CADD	Benign	0.96
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7325983; hg19: chr13-52520627;