NM_000053.4:c.1366G>C

Variant names:

• chr13-51970669-C-G
• rs1801244
• NM_000053.4:c.1366G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.1366G>C​(p.Val456Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,902 control chromosomes in the GnomAD database, including 178,885 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V456V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13491 hom., cov: 32)
  • Exomes 𝑓: 0.47 (165394 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: -0.911
• Publications: 69 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 -19 ACMG points.

• 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=1.083074E-4).
• BP6: Variant 13-51970669-C-G is Benign according to our data. Variant chr13-51970669-C-G is described in ClinVar as Benign. ClinVar VariationId is 35702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 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.1366G>C	p.Val456Leu	missense	Exon 3 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.1366G>C	p.Val456Leu	missense	Exon 4 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.1366G>C	p.Val456Leu	missense	Exon 4 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.1366G>C	p.Val456Leu	missense	Exon 3 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.1366G>C	p.Val456Leu	missense	Exon 3 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.1366G>C	p.Val456Leu	missense	Exon 3 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61848 AN: 151970 Hom.: 13493 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.440 AC: 109640 AN: 249182 AF XY: 0.441

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.472 AC: 689334 AN: 1461814 Hom.: 165394 Cov.: 61 AF XY: 0.469 AC XY: 341034 AN XY: 727208

African (AFR) AF: 0.228 AC: 7632 AN: 33480

American (AMR) AF: 0.393 AC: 17569 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11312 AN: 26132

East Asian (EAS) AF: 0.476 AC: 18906 AN: 39700

South Asian (SAS) AF: 0.344 AC: 29708 AN: 86258

European-Finnish (FIN) AF: 0.527 AC: 28135 AN: 53412

Middle Eastern (MID) AF: 0.465 AC: 2685 AN: 5768

European-Non Finnish (NFE) AF: 0.490 AC: 545191 AN: 1111946

Other (OTH) AF: 0.467 AC: 28196 AN: 60394

GnomAD4 genome AF: 0.407 AC: 61856 AN: 152088 Hom.: 13491 Cov.: 32 AF XY: 0.409 AC XY: 30433 AN XY: 74340

African (AFR) AF: 0.232 AC: 9647 AN: 41498

American (AMR) AF: 0.409 AC: 6256 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3466

East Asian (EAS) AF: 0.487 AC: 2521 AN: 5178

South Asian (SAS) AF: 0.353 AC: 1704 AN: 4822

European-Finnish (FIN) AF: 0.528 AC: 5583 AN: 10568

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33191 AN: 67964

Other (OTH) AF: 0.463 AC: 976 AN: 2110

Alfa AF: 0.430 Hom.: 4418

Bravo AF: 0.393

TwinsUK AF: 0.490 AC: 1818

ALSPAC AF: 0.496 AC: 1913

ESP6500AA AF: 0.224 AC: 887

ESP6500EA AF: 0.492 AC: 4068

ExAC AF: 0.434 AC: 52469

Asia WGS AF: 0.423 AC: 1466 AN: 3478

EpiCase AF: 0.488

EpiControl AF: 0.486

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	5.0
DANN	Benign	0.87
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.91
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Benign	0.60	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.037
MutPred		0.10		Loss of loop (P = 0.0512)
MPC		0.058
ClinPred		0.0082	T
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.078
gMVP		0.28
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1801244; hg19: chr13-52544805; COSMIC: COSV54435164; COSMIC: COSV54435164;