Genetic Variant NM_000053.4:c.2906G>A (chr13-51946438-C-T) – ACMG Classification: Pathogenic (23 pts)

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2906G>A(p.Arg969Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,078 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000916622: R969Q was shown to markedly affect copper transport and lead to hyperphosphorylation (Huster, 2012)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R969W) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 7.86

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

Wilson disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 23 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000916622: R969Q was shown to markedly affect copper transport and lead to hyperphosphorylation (Huster, 2012).; SCV004847827: "In vitro functional studies provide some evidence that this variant impacts protein function (Huster 2012)."; SCV005430253: Functional studies have shown that this variant partially disrupts copper transport and hyperphosphorylation (PMID: 22240481).; SCV006061621: Functional studies have shown that this variant partially disrupts copper transport and hyperphosphorylation (PMID: 22240481).; SCV000329795: Published functional studies demonstrate R969Q has a significant decrease in copper uptake compared to wild-type (PMID: 22240481); SCV005042393: Well-established functional studies show a deleterious effect (PS3).; SCV004719647: two other studies have reported moderate to complete loss of transport function (Huster et al. 2012. PubMed ID: 22240481; Das et al. 2022. PubMed ID: 35762218). Furthermore, ATP7A protein with the p.Arg969Gln variant has been shown to have reduced expression relative to wild type and improper cellular localization to the endoplasmic reticulum (Das et al. 2022. PubMed ID: 35762218).

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-51946439-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381534.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 13-51946438-C-T is Pathogenic according to our data. Variant chr13-51946438-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7B	NM_000053.4	MANE Select	c.2906G>A	p.Arg969Gln	missense	Exon 13 of 21	NP_000044.2	P35670-1
ATP7B	NM_001406511.1		c.2906G>A	p.Arg969Gln	missense	Exon 14 of 22	NP_001393440.1	P35670-1
ATP7B	NM_001406512.1		c.2906G>A	p.Arg969Gln	missense	Exon 14 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2906G>A	p.Arg969Gln	missense	Exon 13 of 21	ENSP00000242839.5	P35670-1
ATP7B	ENST00000634844.1	TSL:1	c.2762G>A	p.Arg921Gln	missense	Exon 13 of 21	ENSP00000489398.1	B7ZLR4
ATP7B	ENST00000448424.7	TSL:1	c.2654G>A	p.Arg885Gln	missense	Exon 11 of 19	ENSP00000416738.3	E7ET55

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000361

AC:

AN:

249470

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000345

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wilson disease (16)

not provided (3)

ATP7B-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.20

PhyloP100

7.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.75

Sift

Benign

0.38

Sift4G

Benign

0.44

Polyphen

1.0

Vest4

0.91

MutPred

0.87

Gain of helix (P = 0.1736)

MVP

0.92

MPC

0.40

ClinPred

0.50

GERP RS

5.2

Varity_R

0.27

gMVP

0.90

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over