rs139211339

Positions:

• chr13-51958298-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000053.4(ATP7B):​c.2355+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,232 control chromosomes in the GnomAD database, including 12 homozygotes. 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 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (8 hom.)
• Consequence: ATP7B NM_000053.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• Conservation: PhyloP100: -0.104

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-51958298-A-C is Benign according to our data. Variant chr13-51958298-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157938.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr13-51958298-A-C is described in Lovd as [Benign]. Variant chr13-51958298-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2355+13T>G		intron_variant		ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2355+13T>G		intron_variant		1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00288 AC: 717 AN: 248902 Hom.: 2 AF XY: 0.00287 AC XY: 388 AN XY: 135128

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00617

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00339 AC: 4947 AN: 1460926 Hom.: 8 Cov.: 30 AF XY: 0.00327 AC XY: 2380 AN XY: 726836

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00563

Gnomad4 NFE exome AF: 0.00384

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74478

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.00420

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00527 Hom.: 2

Bravo AF: 0.00204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2018	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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Wilson disease Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 15, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 02, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2020	- -

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP7B: BS2 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely benign and reported on 09-19-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2016	Variant summary: The ATP7B c.2355+13T>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 357/119646 control chromosomes (1 homozygote), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.0062046 (41/6608). This frequency is about the same frequency as the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. The variant has been reported in the literature without strong evidence for causality, and in one case was present on the same chromosome as a known pathogenic variant, supporting the benign role of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.45
DANN	Benign	0.62

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: rs139211339; hg19: chr13-52532434;