13-51958537-C-G

Variant names:

• chr13-51958537-C-G
• rs1555291285
• NM_000053.4:c.2129G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2129G>C​(p.Gly710Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G710S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 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, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51958538-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 156281.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, 0.985
• PP5: Variant 13-51958537-C-G is Pathogenic according to our data. Variant chr13-51958537-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551497.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.2129G>C	p.Gly710Ala	missense	Exon 8 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.2129G>C	p.Gly710Ala	missense	Exon 9 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.2129G>C	p.Gly710Ala	missense	Exon 9 of 22	NP_001393441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2129G>C	p.Gly710Ala	missense	Exon 8 of 21	ENSP00000242839.5
	ATP7B	ENST00000418097.7	TSL:1	c.2129G>C	p.Gly710Ala	missense	Exon 8 of 20	ENSP00000393343.2
	ATP7B	ENST00000448424.7	TSL:1	c.1877G>C	p.Gly626Ala	missense	Exon 6 of 19	ENSP00000416738.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:6 Uncertain:1

Dec 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with alanine at codon 710 of the ATP7B protein (p.Gly710Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in individuals affected with hepatic Wilson disease (PMID: 9887381, 19596473). ClinVar contains an entry for this variant (Variation ID: 551497). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly710 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 27398169, 8938442, 16233999, 16133174, 10544227, 17433323, 15967699), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with alanine at codon 710 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in an individual affected with Wilson disease (PMID: 19596473). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Gly710Ser, is considered to be disease-causing (ClinVar variation ID: 156281), suggesting that Gly at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

Apr 04, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 26, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 25, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Gain of catalytic residue at G710 (P = 0.0245)
MVP		0.97
MPC		0.39
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.92
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555291285; hg19: chr13-52532673;