Genetic Variant NM_000053.4:c.2973G>A (chr13-51946371-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000053.4(ATP7B):c.2973G>A(p.Thr991Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.067 in 1,613,402 control chromosomes in the GnomAD database, including 4,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T991T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.048 ( 242 hom., cov: 33)

Exomes 𝑓: 0.069 ( 3960 hom. )

Consequence

ATP7B
NM_000053.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -3.41

Publications

16 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 13-51946371-C-T is Benign according to our data. Variant chr13-51946371-C-T is described in ClinVar as Benign. ClinVar VariationId is 35713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.41 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0765 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	UniProt
ATP7B	NM_000053.4	MANE Select	c.2973G>A	p.Thr991Thr	synonymous	Exon 13 of 21	NP_000044.2	P35670-1
ATP7B	NM_001406511.1		c.2973G>A	p.Thr991Thr	synonymous	Exon 14 of 22	NP_001393440.1	P35670-1
ATP7B	NM_001406512.1		c.2973G>A	p.Thr991Thr	synonymous	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.2973G>A	p.Thr991Thr	synonymous	Exon 13 of 21	ENSP00000242839.5	P35670-1
ATP7B	ENST00000634844.1	TSL:1	c.2829G>A	p.Thr943Thr	synonymous	Exon 13 of 21	ENSP00000489398.1	B7ZLR4
ATP7B	ENST00000448424.7	TSL:1	c.2721G>A	p.Thr907Thr	synonymous	Exon 11 of 19	ENSP00000416738.3	E7ET55

Frequencies

GnomAD3 genomes

AF:

0.0485

AC:

7387

AN:

152198

Hom.:

242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0273

Gnomad ASJ

AF:

0.0714

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0562

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0782

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0538

AC:

13350

AN:

248362

AF XY:

0.0568

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0724

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.0402

Gnomad NFE exome

AF:

0.0764

Gnomad OTH exome

AF:

0.0601

GnomAD4 exome

AF:

0.0689

AC:

100710

AN:

1461086

Hom.:

3960

Cov.:

AF XY:

0.0690

AC XY:

50141

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.0105

AC:

353

AN:

33466

American (AMR)

AF:

0.0249

AC:

1113

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0694

AC:

1813

AN:

26126

East Asian (EAS)

AF:

0.000277

AC:

AN:

39696

South Asian (SAS)

AF:

0.0603

AC:

5191

AN:

86154

European-Finnish (FIN)

AF:

0.0426

AC:

2275

AN:

53400

Middle Eastern (MID)

AF:

0.0477

AC:

258

AN:

5408

European-Non Finnish (NFE)

AF:

0.0773

AC:

85991

AN:

1111808

Other (OTH)

AF:

0.0614

AC:

3705

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6193

12386

18580

24773

30966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3066

6132

9198

12264

15330

<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:

0.0485

AC:

7387

AN:

152316

Hom.:

242

Cov.:

AF XY:

0.0455

AC XY:

3390

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0134

AC:

559

AN:

41582

American (AMR)

AF:

0.0272

AC:

417

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0714

AC:

248

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.0563

AC:

272

AN:

4832

European-Finnish (FIN)

AF:

0.0382

AC:

405

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0782

AC:

5320

AN:

68016

Other (OTH)

AF:

0.0425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

368

735

1103

1470

1838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0680

Hom.:

278

Bravo

AF:

0.0452

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0788

EpiControl

AF:

0.0742

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wilson disease (8)

not specified (7)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.34

(source)

DANN

Benign

0.78

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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