rs1801249

Variant names:

• chr13-51941218-A-G
• rs1801249
• NM_000053.4:c.3419T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-51941218-A-G
• chr13-51941218-A-C
• chr13-51941218-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.3419T>C​(p.Val1140Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 1,613,484 control chromosomes in the GnomAD database, including 271,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. V1140S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.57 (24911 hom., cov: 30)
  • Exomes 𝑓: 0.58 (246937 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 0.0310
• Publications: 80 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000053.4
• 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=1.2938263E-5).
• BP6: Variant 13-51941218-A-G is Benign according to our data. Variant chr13-51941218-A-G is described in ClinVar as Benign. ClinVar VariationId is 35720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

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.3419T>C	p.Val1140Ala	missense	Exon 16 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3419T>C	p.Val1140Ala	missense	Exon 17 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3419T>C	p.Val1140Ala	missense	Exon 17 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.3419T>C	p.Val1140Ala	missense	Exon 16 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3275T>C	p.Val1092Ala	missense	Exon 16 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3224T>C	p.Val1075Ala	missense	Exon 15 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86732 AN: 151764 Hom.: 24894 Cov.: 30

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.569 AC: 142081 AN: 249554 AF XY: 0.568

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.397

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.579 AC: 846900 AN: 1461602 Hom.: 246937 Cov.: 56 AF XY: 0.578 AC XY: 420148 AN XY: 727102

African (AFR) AF: 0.559 AC: 18710 AN: 33476

American (AMR) AF: 0.635 AC: 28420 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 15001 AN: 26134

East Asian (EAS) AF: 0.402 AC: 15953 AN: 39694

South Asian (SAS) AF: 0.521 AC: 44936 AN: 86254

European-Finnish (FIN) AF: 0.607 AC: 32397 AN: 53406

Middle Eastern (MID) AF: 0.633 AC: 3652 AN: 5766

European-Non Finnish (NFE) AF: 0.587 AC: 652963 AN: 1111764

Other (OTH) AF: 0.577 AC: 34868 AN: 60386

GnomAD4 genome AF: 0.571 AC: 86795 AN: 151882 Hom.: 24911 Cov.: 30 AF XY: 0.571 AC XY: 42376 AN XY: 74224

African (AFR) AF: 0.556 AC: 22996 AN: 41390

American (AMR) AF: 0.602 AC: 9188 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3472

East Asian (EAS) AF: 0.408 AC: 2100 AN: 5152

South Asian (SAS) AF: 0.524 AC: 2517 AN: 4808

European-Finnish (FIN) AF: 0.602 AC: 6349 AN: 10550

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39839 AN: 67930

Other (OTH) AF: 0.595 AC: 1253 AN: 2106

Alfa AF: 0.573 Hom.: 99814

Bravo AF: 0.573

TwinsUK AF: 0.586 AC: 2173

ALSPAC AF: 0.590 AC: 2274

ESP6500AA AF: 0.548 AC: 2112

ESP6500EA AF: 0.591 AC: 4888

ExAC AF: 0.565 AC: 68274

Asia WGS AF: 0.529 AC: 1836 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.591

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Wilson disease (9)
-	-	8	not specified (8)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.6
DANN	Benign	0.24
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.0056	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.15	N
PhyloP100		0.031
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.19
Sift	Benign	0.91	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MPC		0.069
ClinPred		0.00030	T
GERP RS		0.087
Varity_R		0.030
gMVP		0.38
Mutation Taster		=97/3	polymorphism (auto)

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: rs1801249; hg19: chr13-52515354; COSMIC: COSV54438812; COSMIC: COSV54438812;