rs587783313

Variant names:

• chr13-51941209-G-T
• rs587783313
• NM_000053.4:c.3428C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Moderate BP6_Moderate

The NM_000053.4(ATP7B):​c.3428C>A​(p.Thr1143Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1143S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16652542).
• BP6: Variant 13-51941209-G-T is Benign according to our data. Variant chr13-51941209-G-T is described in ClinVar as Benign. ClinVar VariationId is 157950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3428C>A	p.Thr1143Asn	missense_variant	Exon 16 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3428C>A	p.Thr1143Asn	missense_variant	Exon 16 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;D;.;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0033
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.72	N;.;.;.;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;N;N;N;N;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.20	T;T;T;T;T;.;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T
Polyphen		0.0070	B;P;P;B;P;B;P
Vest4		0.21
MutPred		0.17		Loss of loop (P = 0.0203);.;.;.;.;.;.;
MVP		0.95
MPC		0.24
ClinPred		0.46	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.74
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs587783313; hg19: chr13-52515345;