rs140708492

Positions:

• chr13-51939199-G-A

Variant summary

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

The NM_000053.4(ATP7B):​c.3557-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,612,598 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: ATP7B NM_000053.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001639
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: 0.0290

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=-0.83).
• BP6: Variant 13-51939199-G-A is Benign according to our data. Variant chr13-51939199-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35722.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=4}. Variant chr13-51939199-G-A is described in Lovd as [Likely_benign]. Variant chr13-51939199-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3557-6C>T		splice_region_variant, 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.3557-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152204 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00255 AC: 631 AN: 247892 Hom.: 1 AF XY: 0.00262 AC XY: 353 AN XY: 134696

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.00391 AC: 5716 AN: 1460276 Hom.: 17 Cov.: 32 AF XY: 0.00393 AC XY: 2857 AN XY: 726562

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00340

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00458

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00312 AC: 476 AN: 152322 Hom.: 4 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74486

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00303 Hom.: 0

Bravo AF: 0.00360

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:3 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant causes a C to T nucleotide substitution at the -6 position of intron 16 of the ATP7B gene. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 12 nucleotides upstream of the native intron 16 splice donor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with Wilson disease, however, the authors described this variant as non-disease causing (PMID: 24094725). This variant has been identified in 706/279290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2023	This variant causes a C to T nucleotide substitution at the -6 position of intron 16 of the ATP7B gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with Wilson disease, however, the authors described this variant as non-disease causing (PMID: 24094725). This variant has been identified in 706/279290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	- -
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, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ATP7B: BP4, BS2 -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2016	Variant summary: The c.c.3557-6C>T variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that is not widely known to affect splicing, 4/5 splicing prediction tools predict no significant effect on splicing, and Mutation Taster predicts the variant to be a polymorphism. This variant was found in 324/122184 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037672 (250/66362). This subpopulation frequency is lower than the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006), but is high enough to suggest that variant could possibly be a benign polymorphism. Additionally, the variant is regarded as a benign variant in literature (Thomas _1995; Mukherjee_2014) and in at least one database (University of Alberta WD database); however no definite evidence was provided to independently evaluate. There was an internal finding that two variants (c.1922T>C (VUS) and c.2731-2A>G (disease variant)) were identified to co-occur with the variant of interest in a subject undergoing ATP7B gene testing. These variants may explain WD phenotype, albeit phase of the variants would need to be assessed and c.1922T>C has not yet been classified as a disease variant. Taken together, this variant has been classified as a VUS-possibly benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.94
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
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: rs140708492; hg19: chr13-52513335;