rs60986317

Variant names:

• chr13-51934853-G-A
• rs60986317
• NM_000053.4:c.4301C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-51934853-G-A
• chr13-51934853-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000053.4(ATP7B):​c.4301C>T​(p.Thr1434Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,208 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1434P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:13
• Conservation: PhyloP100: 1.47
• Publications: 29 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 -8 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=0.008024335).
• BP6: Variant 13-51934853-G-A is Benign according to our data. Variant chr13-51934853-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35730.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.4301C>T	p.Thr1434Met	missense	Exon 21 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.4301C>T	p.Thr1434Met	missense	Exon 22 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.4301C>T	p.Thr1434Met	missense	Exon 22 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.4301C>T	p.Thr1434Met	missense	Exon 21 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.4157C>T	p.Thr1386Met	missense	Exon 21 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.4106C>T	p.Thr1369Met	missense	Exon 20 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00197 AC: 491 AN: 249530 AF XY: 0.00179

Gnomad AFR exome AF: 0.00528

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00119 AC: 1745 AN: 1461840 Hom.: 4 Cov.: 30 AF XY: 0.00114 AC XY: 831 AN XY: 727226

African (AFR) AF: 0.00421 AC: 141 AN: 33480

American (AMR) AF: 0.00387 AC: 173 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00934 AC: 244 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53384

Middle Eastern (MID) AF: 0.00591 AC: 34 AN: 5756

European-Non Finnish (NFE) AF: 0.000848 AC: 943 AN: 1112008

Other (OTH) AF: 0.00257 AC: 155 AN: 60394

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152368 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74510

African (AFR) AF: 0.00527 AC: 219 AN: 41592

American (AMR) AF: 0.00412 AC: 63 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68036

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00173 Hom.: 2

Bravo AF: 0.00303

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00504 AC: 22

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.00190 AC: 230

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	5	Wilson disease (10)
-	2	5	not provided (7)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.097
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.093	T
Sift4G	Benign	0.24	T
Polyphen		0.89	P
Vest4		0.19
MVP		0.84
MPC		0.30
ClinPred		0.018	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.12
Mutation Taster		=99/1	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: rs60986317; hg19: chr13-52508989;