NM_000053.4:c.1216T>G

Variant names:

• chr13-51974004-A-C
• rs1801243
• NM_000053.4:c.1216T>G

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.1216T>G​(p.Ser406Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,614,028 control chromosomes in the GnomAD database, including 184,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S406T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13523 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170543 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: -1.55
• Publications: 78 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: 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=4.1596646E-5).
• BP6: Variant 13-51974004-A-C is Benign according to our data. Variant chr13-51974004-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.1216T>G	p.Ser406Ala	missense	Exon 3 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.1216T>G	p.Ser406Ala	missense	Exon 3 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.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 21	ENSP00000489398.1
	ATP7B	ENST00000418097.7	TSL:1	c.1216T>G	p.Ser406Ala	missense	Exon 2 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60992 AN: 152042 Hom.: 13529 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.455

GnomAD2 exomes AF: 0.445 AC: 111028 AN: 249516 AF XY: 0.446

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.478 AC: 698979 AN: 1461868 Hom.: 170543 Cov.: 73 AF XY: 0.476 AC XY: 345879 AN XY: 727236

African (AFR) AF: 0.186 AC: 6221 AN: 33480

American (AMR) AF: 0.391 AC: 17481 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 11475 AN: 26136

East Asian (EAS) AF: 0.525 AC: 20825 AN: 39700

South Asian (SAS) AF: 0.350 AC: 30224 AN: 86258

European-Finnish (FIN) AF: 0.535 AC: 28578 AN: 53420

Middle Eastern (MID) AF: 0.453 AC: 2611 AN: 5766

European-Non Finnish (NFE) AF: 0.497 AC: 553096 AN: 1111990

Other (OTH) AF: 0.471 AC: 28468 AN: 60396

GnomAD4 genome AF: 0.401 AC: 60988 AN: 152160 Hom.: 13523 Cov.: 33 AF XY: 0.404 AC XY: 30026 AN XY: 74388

African (AFR) AF: 0.192 AC: 7982 AN: 41538

American (AMR) AF: 0.404 AC: 6172 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1530 AN: 3464

East Asian (EAS) AF: 0.540 AC: 2794 AN: 5172

South Asian (SAS) AF: 0.359 AC: 1729 AN: 4820

European-Finnish (FIN) AF: 0.538 AC: 5697 AN: 10582

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33642 AN: 67978

Other (OTH) AF: 0.454 AC: 956 AN: 2108

Alfa AF: 0.459 Hom.: 55599

Bravo AF: 0.385

TwinsUK AF: 0.494 AC: 1833

ALSPAC AF: 0.508 AC: 1956

ESP6500AA AF: 0.186 AC: 720

ESP6500EA AF: 0.502 AC: 4158

ExAC AF: 0.438 AC: 52986

Asia WGS AF: 0.429 AC: 1489 AN: 3478

EpiCase AF: 0.494

EpiControl AF: 0.491

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.049
Sift	Benign	0.75	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.018
MPC		0.053
ClinPred		0.0092	T
GERP RS		-0.027
Varity_R		0.051
gMVP		0.19
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1801243; hg19: chr13-52548140; COSMIC: COSV54438507; COSMIC: COSV54438507;