Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000053.4(ATP7B):c.1216T>G(p.Ser406Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,614,028 control chromosomes in the GnomAD database, including 184,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S406T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 13523 hom., cov: 33)

Exomes 𝑓: 0.48 ( 170543 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:20

Conservation

PhyloP100: -1.55

Publications

78 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, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=4.1596646E-5).

BP6

Variant 13-51974004-A-C is Benign according to our data. Variant chr13-51974004-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

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
ATP7B	NM_000053.4	MANE Select	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	NP_000044.2
ATP7B	NM_001406511.1		c.1216T>G	p.Ser406Ala	missense	Exon 3 of 22	NP_001393440.1
ATP7B	NM_001406512.1		c.1216T>G	p.Ser406Ala	missense	Exon 3 of 22	NP_001393441.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	ENSP00000242839.5
ATP7B	ENST00000634844.1	TSL:1	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	ENSP00000489398.1
ATP7B	ENST00000418097.7	TSL:1	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60992

AN:

152042

Hom.:

13529

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.442

Gnomad EAS

AF:

0.541

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.538

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.495

Gnomad OTH

AF:

0.455

GnomAD2 exomes

AF:

0.445

AC:

111028

AN:

249516

AF XY:

0.446

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.440

Gnomad EAS exome

AF:

0.533

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.490

Gnomad OTH exome

AF:

0.471

GnomAD4 exome

AF:

0.478

AC:

698979

AN:

1461868

Hom.:

170543

Cov.:

AF XY:

0.476

AC XY:

345879

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.186

AC:

6221

AN:

33480

American (AMR)

AF:

0.391

AC:

17481

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

11475

AN:

26136

East Asian (EAS)

AF:

0.525

AC:

20825

AN:

39700

South Asian (SAS)

AF:

0.350

AC:

30224

AN:

86258

European-Finnish (FIN)

AF:

0.535

AC:

28578

AN:

53420

Middle Eastern (MID)

AF:

0.453

AC:

2611

AN:

5766

European-Non Finnish (NFE)

AF:

0.497

AC:

553096

AN:

1111990

Other (OTH)

AF:

0.471

AC:

28468

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

25023

50046

75070

100093

125116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15944

31888

47832

63776

79720

<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:

0.401

AC:

60988

AN:

152160

Hom.:

13523

Cov.:

AF XY:

0.404

AC XY:

30026

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.192

AC:

7982

AN:

41538

American (AMR)

AF:

0.404

AC:

6172

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.442

AC:

1530

AN:

3464

East Asian (EAS)

AF:

0.540

AC:

2794

AN:

5172

South Asian (SAS)

AF:

0.359

AC:

1729

AN:

4820

European-Finnish (FIN)

AF:

0.538

AC:

5697

AN:

10582

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.495

AC:

33642

AN:

67978

Other (OTH)

AF:

0.454

AC:

956

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1806

3612

5419

7225

9031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.459

Hom.:

55599

Bravo

AF:

0.385

TwinsUK

AF:

0.494

AC:

1833

ALSPAC

AF:

0.508

AC:

1956

ESP6500AA

AF:

0.186

AC:

720

ESP6500EA

AF:

0.502

AC:

4158

ExAC

AF:

0.438

AC:

52986

Asia WGS

AF:

0.429

AC:

1489

AN:

3478

EpiCase

AF:

0.494

EpiControl

AF:

0.491

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Wilson disease (9)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.6

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.42

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.22

MetaRNN

Benign

0.000042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-1.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.20

REVEL

Benign

0.049

Sift

Benign

0.75

Sift4G

Benign

0.77

Polyphen

0.0010

Vest4

0.018

MPC

0.053

ClinPred

0.0092

GERP RS

-0.027

Varity_R

0.051

gMVP

0.19

Mutation Taster

=94/6

polymorphism (auto)

(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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rs1801243

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over