rs370579582

chr13-51973930-C-Achr13-51973930-C-Gchr13-51973930-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.1285+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000812 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 13-51973930-C-A is Pathogenic according to our data. Variant chr13-51973930-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51973930-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.1285+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1285+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000562

AC:

AN:

249066

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000841

AC:

123

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000816

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:10

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: ATP7B c.1285+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts the variant weakens this canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 249066 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (5.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.1285+5G>T has been reported in the literature in several compound heterozygous individuals affected with Wilson Disease (e.g. Loudianos_1998, Ivanova_2015, Paradisi_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, five classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change falls in intron 2 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370579582, gnomAD 0.009%). This variant has been observed in individual(s) with Wilson disease (PMID: 9671269, 25497208, 25617204, 36096368). This variant is also known as IVS2+5G-T. ClinVar contains an entry for this variant (Variation ID: 520762). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated Wilson disease (MIM#277900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in at least five individuals with Wilson disease (MIM#277900) (ClinVar, HGMD, LOVD, PMID: 9671269, PMID: 25497208). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 06, 2022	_x000D_This variant was identified with NM_000053.4:c.3451C>T, phase is unknown. Both variants were reported as secondary findings in a patient without Wilson associated symptoms Criteria applied: PM3_STR, PM2_SUP, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.1285+5G>T variant in ATP7B has been previously reported in 2 individuals with Wilson disease who were compound heterozygous for a second pathogenic variant (Ivanova 2015 PMID: 25617204, Paradisi 2015 PMID: 25497208). It has also been identified in 0.008% (3/35374) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele. This variant is located in the 5' splice region. Computational tools predict a splicing impact. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Splice variant was predicted to result in a truncated protein by alternate splicing. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.78). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000520762). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant causes a G to T nucleotide substitution at the +5 position of intron 2 of the ATP7B gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in four individuals affected with autosomal recessive Wilson disease, including two individuals who were compound heterozygous with a known pathogenic variant in the same gene (PMID: 9671269, 25497208, 25617204, 36096368). This variant has been identified in 16/280466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10502776, 18728530, 34426522, 25497208, 25617204, 9671269, 36096368, 17576681, 9536098) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2024	PM3_strong, PS4_moderate, PM2_supporting, PP4, PP3, PP1 -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2020

The c.1285+5G>T intronic alteration consists of a G to T substitution nucleotides after coding exon 2 in the ATP7B gene. This alteration is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the ATP7B c.1285+5G>T alteration was observed in 1 among 12360 total alleles studied (0.01%), having only been observed in 8346 European American alleles. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Based on data from the Exome Aggregation Consortium (ExAC), the T allele was observed in 5 of 120,746 total alleles studied, having been observed in 1 out of 16512 South Asian alleles, and 4 out of 66,724 European (Non-Finnish) alleles. This variant is reported in the SNPDatabase as rs370579582. This splice site alteration has been observed in affected individuals: _x000D_ This alteration was observed in the heterozygous state in one individual from a cohort of individuals diagnosed with WIlson disease based on low ceruloplasmin and copper serum levels, high urinary copper elimination, and high hepatic copper content. However, the authors did not report if there was a second mutation detected in this individual (Loudianos, 1998). Ivanova et al. (2015) described a case in which a 26 year old man was found to have this alteration along with p.L936X, although phase was not confirmed. He presented with chronic hepatitis and steatosis, low ceruloplasmin level, and increased copper urinary excretion but lacked any ocular findings of Wilson disease. He also presented with multiple non-tender skin papules located on his back and trunk consistent with a diagnosis of primary anetoderma. A Venezuelan and Colombian woman was found to have this alteration in trans with a frameshift mutation. She had classic metabolic findings as well as neurological disease, although lacked any liver complications (Paradisi, 2015). The altered nucleotide is conserved throughout evolution:_x000D_ The c.1285+5G nucleotide is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ The c.1285+5G>T alteration is predicted to abolish the donor splice site using Fruitfly in silico program. The ESEfinder 3.0 in silico program predicts a weakening of the donor splice site. Based on the available evidence, this alteration is classified as likely pathogenic. -

ATP7B-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

The ATP7B c.1285+5G>T variant is predicted to interfere with splicing. This variant has been reported along with a second pathogenic ATP7B variant in two individuals with Wilson Disease, one of which also presented with anetoderma (referred to as IVS2+5G>T, Ivanova et al. 2015. PubMed ID: 25617204; Paradisi et al. 2015. PubMed ID: 25497208). It has also been observed in other individuals with Wilson Disease; however, it was unclear whether a second causative allele was identified (Loudianos et al.1998. PubMed ID: 9671269; Supplementary Table 1, Nayagam et al. 2023. PubMed ID: 36096368). Internally, we have observed this variant in the heterozygous state along with a second pathogenic variant in two affected individuals. Several splicing prediction programs indicate that this variant may abolish the canonical splice donor site at the junction of exon 2 and intron 2 (Alamut Visual v2.11). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. Taken together, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.78

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over