NM_000053.4:c.4021+50G>C

Variant names:

• chr13-51937226-C-G
• rs9535795
• NM_000053.4:c.4021+50G>C

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.4021+50G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,565,232 control chromosomes in the GnomAD database, including 262,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24230 hom., cov: 30)
  • Exomes 𝑓: 0.58 (238167 hom.)
• Consequence: ATP7B NM_000053.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.499
• Publications: 13 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=-0.9).
• BP6: Variant 13-51937226-C-G is Benign according to our data. Variant chr13-51937226-C-G is described in ClinVar as Benign. ClinVar VariationId is 254770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.4021+50G>C		intron_variant	Intron 19 of 20	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.4021+50G>C		intron_variant	Intron 19 of 20	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85469 AN: 151626 Hom.: 24220 Cov.: 30

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.651

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.584

GnomAD2 exomes AF: 0.566 AC: 140122 AN: 247424 AF XY: 0.565

Gnomad AFR exome AF: 0.522

Gnomad AMR exome AF: 0.634

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.578 AC: 817418 AN: 1413492 Hom.: 238167 Cov.: 28 AF XY: 0.577 AC XY: 407071 AN XY: 705734

African (AFR) AF: 0.533 AC: 17276 AN: 32422

American (AMR) AF: 0.633 AC: 28185 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14811 AN: 25834

East Asian (EAS) AF: 0.402 AC: 15826 AN: 39406

South Asian (SAS) AF: 0.521 AC: 44332 AN: 85140

European-Finnish (FIN) AF: 0.606 AC: 32344 AN: 53336

Middle Eastern (MID) AF: 0.631 AC: 3584 AN: 5682

European-Non Finnish (NFE) AF: 0.587 AC: 627251 AN: 1068322

Other (OTH) AF: 0.575 AC: 33809 AN: 58818

GnomAD4 genome AF: 0.564 AC: 85523 AN: 151740 Hom.: 24230 Cov.: 30 AF XY: 0.563 AC XY: 41754 AN XY: 74102

African (AFR) AF: 0.530 AC: 21898 AN: 41350

American (AMR) AF: 0.597 AC: 9119 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1967 AN: 3464

East Asian (EAS) AF: 0.407 AC: 2092 AN: 5142

South Asian (SAS) AF: 0.523 AC: 2509 AN: 4796

European-Finnish (FIN) AF: 0.602 AC: 6306 AN: 10474

Middle Eastern (MID) AF: 0.648 AC: 188 AN: 290

European-Non Finnish (NFE) AF: 0.586 AC: 39816 AN: 67924

Other (OTH) AF: 0.586 AC: 1238 AN: 2112

Alfa AF: 0.576 Hom.: 4665

Bravo AF: 0.563

Asia WGS AF: 0.526 AC: 1824 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

Wilson disease Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.82
DANN	Benign	0.49
PhyloP100		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9535795; hg19: chr13-52511362; COSMIC: COSV54442967; COSMIC: COSV54442967;