dbSNP rs145798966: ATP7B:p.Leu540Leu (chr13-51968531-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000053.4(ATP7B):c.1620C>T(p.Leu540Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L540L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

ATP7B
NM_000053.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13

Conservation

PhyloP100: -2.31

Publications

10 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 13-51968531-G-A is Benign according to our data. Variant chr13-51968531-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254760.

BP7

Synonymous conserved (PhyloP=-2.31 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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.1620C>T	p.Leu540Leu	synonymous	Exon 4 of 21	NP_000044.2
ATP7B	NM_001406511.1		c.1620C>T	p.Leu540Leu	synonymous	Exon 5 of 22	NP_001393440.1
ATP7B	NM_001406512.1		c.1620C>T	p.Leu540Leu	synonymous	Exon 5 of 22	NP_001393441.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.1620C>T	p.Leu540Leu	synonymous	Exon 4 of 21	ENSP00000242839.5
ATP7B	ENST00000634844.1	TSL:1	c.1620C>T	p.Leu540Leu	synonymous	Exon 4 of 21	ENSP00000489398.1
ATP7B	ENST00000418097.7	TSL:1	c.1620C>T	p.Leu540Leu	synonymous	Exon 4 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00146

AC:

363

AN:

249476

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00201

AC:

2945

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1396

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00136

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00247

AC:

2749

AN:

1112012

Other (OTH)

AF:

0.00172

AC:

104

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00144

AC:

219

AN:

152258

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41552

American (AMR)

AF:

0.00170

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00241

AC:

164

AN:

68010

Other (OTH)

AF:

0.00331

AC:

AN:

2112

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:

0.00139

Hom.:

Bravo

AF:

0.00144

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00219

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wilson disease (7)

not provided (5)

not specified (4)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.39

(source)

DANN

Benign

0.43

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism

(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