13-51944231-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000053.4(ATP7B):ā€‹c.3121C>Gā€‹(p.Arg1041Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

6
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.491
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP7BNM_000053.4 linkc.3121C>G p.Arg1041Gly missense_variant Exon 14 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.3121C>G p.Arg1041Gly missense_variant Exon 14 of 21 1 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248998
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135292
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461808
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000826
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.92
D;D;.;.;.;.;.
Eigen
Benign
-0.049
Eigen_PC
Benign
-0.071
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Benign
0.47
N;.;.;.;.;.;.
PrimateAI
Benign
0.47
T
PROVEAN
Pathogenic
-5.5
D;D;D;D;D;.;D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0040
D;D;D;D;D;.;D
Sift4G
Uncertain
0.047
D;D;D;D;D;T;T
Polyphen
1.0
D;D;D;B;D;P;D
Vest4
0.76
MutPred
0.83
Gain of catalytic residue at V1042 (P = 0.0151);.;.;.;.;.;.;
MVP
0.99
MPC
0.42
ClinPred
0.91
D
GERP RS
1.0
Varity_R
0.75
gMVP
0.92

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: rs746485916; hg19: chr13-52518367; API