rs374628199

Variant names:

• chr13-51937663-A-C
• rs374628199
• NM_000053.4:c.3716T>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5

The NM_000053.4(ATP7B):​c.3716T>G​(p.Val1239Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,106 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000626858: Experimental studies have shown that this missense change affects ATP7B function (PMID:22692182)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1239F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 7.51
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000626858: Experimental studies have shown that this missense change affects ATP7B function (PMID: 22692182).; SCV004841132: "A functional study in yeast has shown that this variant results in the lack of ATP7B protein expression and inability to complement ccc2 deficiency (PMID: 20333758)."; SCV005876974: "in vitro functional analyses demonstrate low protein expression and a deleterious effect on protein function (Luoma 2010)."; SCV006061546: "A functional study in yeast has shown that this variant results in the lack of ATP7B protein expression and inability to complement ccc2 deficiency (PMID: 20333758)."; SCV002619529: Functional studies of this alteration showed low protein expression and a deleterious impact on the protein function (Luoma LM, Hum. Mutat. 2010 May; 31(5):569-77).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.939
• PP5: Variant 13-51937663-A-C is Pathogenic according to our data. Variant chr13-51937663-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456557.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.3716T>G	p.Val1239Gly	missense	Exon 18 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3716T>G	p.Val1239Gly	missense	Exon 19 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3716T>G	p.Val1239Gly	missense	Exon 19 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.3716T>G	p.Val1239Gly	missense	Exon 18 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3572T>G	p.Val1191Gly	missense	Exon 18 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3521T>G	p.Val1174Gly	missense	Exon 17 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249548 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000757 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	3	-	Wilson disease (8)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.99
MPC		0.42
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.96
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs374628199; hg19: chr13-52511799;