13-51958492-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_000053.4(ATP7B):c.2174G>A(p.Arg725Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R725S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.434

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009857595).

BP6

Variant 13-51958492-C-T is Benign according to our data. Variant chr13-51958492-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456551.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2174G>A	p.Arg725Lys	missense_variant	8/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2174G>A	p.Arg725Lys	missense_variant	8/21	1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

249556

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.00232

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152328

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00267

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000695

ESP6500AA

AF:

0.00143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2023	The ATP7B c.2174G>A; p.Arg725Lys variant (rs115227204), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 456551). This variant is found in the African/African-American population with an allele frequency of 0.3% (63/24202 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.158). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

Cadd

Benign

8.3

Dann

Benign

0.73

DEOGEN2

Benign

0.39

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.45

N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;P;B

Vest4

0.21

MVP

0.76

MPC

0.060

ClinPred

0.0066

GERP RS

0.18

Varity_R

0.060

gMVP

0.65

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.

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