rs372456815

chr13-51942474-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000053.4(ATP7B):c.3324C>T(p.Asn1108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.0620

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 13-51942474-G-A is Benign according to our data. Variant chr13-51942474-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr13-51942474-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.062 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3324C>T	p.Asn1108=	synonymous_variant	15/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3324C>T	p.Asn1108=	synonymous_variant	15/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000349 AC: 87 AN: 249568 Hom.: 0 AF XY: 0.000318 AC XY: 43 AN XY: 135404

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000468

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000356 AC: 521 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.000356 AC XY: 259 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74500

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000230

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 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	-0.48
Cadd	Benign	4.4
Dann	Benign	0.72
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: rs372456815; hg19: chr13-52516610;