chr13-51937490-C-T

Variant names:

• chr13-51937490-C-T
• rs148399850
• NM_000053.4:c.3889G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000053.4(ATP7B):​c.3889G>A​(p.Val1297Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,090 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1297V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (9 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 1.74
• 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 -10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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=0.012555271).
• BP6: Variant 13-51937490-C-T is Benign according to our data. Variant chr13-51937490-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92389.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00207 (316/152350) while in subpopulation EAS AF = 0.0206 (107/5186). AF 95% confidence interval is 0.0175. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.3889G>A	p.Val1297Ile	missense	Exon 18 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3889G>A	p.Val1297Ile	missense	Exon 19 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3889G>A	p.Val1297Ile	missense	Exon 19 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.3889G>A	p.Val1297Ile	missense	Exon 18 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3745G>A	p.Val1249Ile	missense	Exon 18 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3694G>A	p.Val1232Ile	missense	Exon 17 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152232 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00240 AC: 598 AN: 249440 AF XY: 0.00228

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00928

Gnomad NFE exome AF: 0.000397

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00105 AC: 1531 AN: 1461740 Hom.: 9 Cov.: 35 AF XY: 0.00107 AC XY: 777 AN XY: 727168

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0170 AC: 674 AN: 39700

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86254

European-Finnish (FIN) AF: 0.00780 AC: 416 AN: 53310

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000202 AC: 225 AN: 1111978

Other (OTH) AF: 0.00136 AC: 82 AN: 60394

GnomAD4 genome AF: 0.00207 AC: 316 AN: 152350 Hom.: 2 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74506

African (AFR) AF: 0.000529 AC: 22 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5186

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68042

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.00120

ESP6500AA AF: 0.000702 AC: 3

ESP6500EA AF: 0.000354 AC: 3

ExAC AF: 0.00225 AC: 272

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	Wilson disease (9)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	-0.030	N
PhyloP100		1.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.51
Sift	Benign	0.35	T
Sift4G	Benign	0.73	T
Polyphen		0.87	P
Vest4		0.46
MVP		0.52
MPC		0.055
ClinPred		0.029	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.51
Mutation Taster		=93/7	polymorphism

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: rs148399850; hg19: chr13-52511626;