13-51937561-G-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.3818C>A​(p.Pro1273Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

ATP7B
NM_000053.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.94
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]

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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
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 13-51937561-G-T is Pathogenic according to our data. Variant chr13-51937561-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP7BNM_000053.4 linkc.3818C>A p.Pro1273Gln missense_variant Exon 18 of 21 ENST00000242839.10 NP_000044.2 P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkc.3818C>A p.Pro1273Gln missense_variant Exon 18 of 21 1 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
35
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:5
Mar 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1273 of the ATP7B protein (p.Pro1273Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 16696937, 18483695, 25465132, 27398169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553360). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22692182). This variant disrupts the p.Pro1273 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024742, 17272994, 20485189, 23551039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Aug 16, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 07, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ATP7B c.3818C>A (p.Pro1273Gln) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249564 control chromosomes (gnomAD). c.3818C>A has been reported in the literature in two homozygous individuals affected with Wilson Disease (example: El-Mougy_2014) and the variant seggregated with the disease. These data indicate that the variant is likely to be associated with disease. Schushan_2012 demonstrated that P1273 changes to S/L/Q leads to very low copper uptake. Another variant affecting the same codon has been classified as pathogenic by our lab (p.Pro1273Leu). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 10, 2021
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 04, 2024
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.71 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000553360 /PMID: 16696937). Different missense changes at the same codon (p.Pro1273Leu, p.Pro1273Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189139 /PMID: 14974157, 8931691). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.97
D;D;.;.;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
1.0
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M;.;.;.;.;.;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-7.3
D;D;D;D;D;.;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D;D;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D
Vest4
0.94
MutPred
0.96
Gain of catalytic residue at P1273 (P = 0.0143);.;.;.;.;.;.;
MVP
1.0
MPC
0.37
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.88

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

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

Other links and lift over

dbSNP: rs758355520; hg19: chr13-52511697; COSMIC: COSV105842016; COSMIC: COSV105842016; API