13-51949772-G-C

Variant names:

• chr13-51949772-G-C
• rs121907993
• NM_000053.4:c.2755C>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2755C>G​(p.Arg919Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,962 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: "SCV000694428: A functional study does implicate the variant to negatively affect wild type function." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R919Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.22
• Publications: 53 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000694428: A functional study does implicate the variant to negatively affect wild type function.; SCV004845482: Functional studies have shown that his variant causes higher levels of copper and normal sub-cellular localization compared to wild type (PMID: 26032686).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51949772-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 312386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.963
• PP5: Variant 13-51949772-G-C is Pathogenic according to our data. Variant chr13-51949772-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3857.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.2755C>G	p.Arg919Gly	missense	Exon 12 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2755C>G	p.Arg919Gly	missense	Exon 13 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2755C>G	p.Arg919Gly	missense	Exon 13 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.2755C>G	p.Arg919Gly	missense	Exon 12 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2611C>G	p.Arg871Gly	missense	Exon 12 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2755C>G	p.Arg919Gly	missense	Exon 12 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 248730 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461750 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727168

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: 26134

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74418

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Wilson disease (9)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.83	P
Vest4		0.67
MutPred		0.94		Loss of stability (P = 0.0472)
MVP		0.97
MPC		0.35
ClinPred		0.87	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.83
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.010		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: rs121907993; hg19: chr13-52523908; COSMIC: COSV54437726; COSMIC: COSV54437726;