13-51937488-G-A

Variant names:

• chr13-51937488-G-A
• rs114771537
• NM_000053.4:c.3891C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000053.4(ATP7B):​c.3891C>T​(p.Val1297Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,064 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -4.48
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-51937488-G-A is Benign according to our data. Variant chr13-51937488-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00983 (1497/152342) while in subpopulation AFR AF = 0.0341 (1419/41572). AF 95% confidence interval is 0.0327. There are 30 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.3891C>T	p.Val1297Val	synonymous	Exon 18 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3891C>T	p.Val1297Val	synonymous	Exon 19 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3891C>T	p.Val1297Val	synonymous	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.3891C>T	p.Val1297Val	synonymous	Exon 18 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3747C>T	p.Val1249Val	synonymous	Exon 18 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3696C>T	p.Val1232Val	synonymous	Exon 17 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00980 AC: 1492 AN: 152224 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00257 AC: 640 AN: 249408 AF XY: 0.00184

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1461722 Hom.: 22 Cov.: 35 AF XY: 0.000923 AC XY: 671 AN XY: 727158

African (AFR) AF: 0.0369 AC: 1234 AN: 33478

American (AMR) AF: 0.00179 AC: 80 AN: 44720

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

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

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

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111980

Other (OTH) AF: 0.00270 AC: 163 AN: 60394

GnomAD4 genome AF: 0.00983 AC: 1497 AN: 152342 Hom.: 30 Cov.: 32 AF XY: 0.00936 AC XY: 697 AN XY: 74494

African (AFR) AF: 0.0341 AC: 1419 AN: 41572

American (AMR) AF: 0.00353 AC: 54 AN: 15302

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68042

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00469 Hom.: 7

Bravo AF: 0.0113

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Wilson disease (6)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	ATP7B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.68
PhyloP100		-4.5
Mutation Taster		=98/2	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: rs114771537; hg19: chr13-52511624;