rs73202048

Variant names:

• chr13-51934843-C-T
• rs73202048
• NM_000053.4:c.4311G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000053.4(ATP7B):​c.4311G>A​(p.Lys1437Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 1,614,196 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., cov: 33)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.37
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 13-51934843-C-T is Benign according to our data. Variant chr13-51934843-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00714 (1088/152356) while in subpopulation NFE AF = 0.0116 (786/68034). AF 95% confidence interval is 0.0109. There are 4 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.4311G>A	p.Lys1437Lys	synonymous	Exon 21 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.4311G>A	p.Lys1437Lys	synonymous	Exon 22 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.4311G>A	p.Lys1437Lys	synonymous	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.4311G>A	p.Lys1437Lys	synonymous	Exon 21 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.4167G>A	p.Lys1389Lys	synonymous	Exon 21 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.4116G>A	p.Lys1372Lys	synonymous	Exon 20 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152238 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00709 AC: 1770 AN: 249562 AF XY: 0.00742

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00553

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00995 AC: 14547 AN: 1461840 Hom.: 90 Cov.: 30 AF XY: 0.00975 AC XY: 7091 AN XY: 727222

African (AFR) AF: 0.00131 AC: 44 AN: 33480

American (AMR) AF: 0.00297 AC: 133 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00590 AC: 509 AN: 86258

European-Finnish (FIN) AF: 0.00598 AC: 319 AN: 53380

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.0117 AC: 13042 AN: 1112008

Other (OTH) AF: 0.00760 AC: 459 AN: 60394

GnomAD4 genome AF: 0.00714 AC: 1088 AN: 152356 Hom.: 4 Cov.: 33 AF XY: 0.00658 AC XY: 490 AN XY: 74500

African (AFR) AF: 0.00240 AC: 100 AN: 41590

American (AMR) AF: 0.00569 AC: 87 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0116 AC: 786 AN: 68034

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00839 Hom.: 7

Bravo AF: 0.00686

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0118

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Wilson disease (8)
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.41
PhyloP100		2.4
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs73202048; hg19: chr13-52508979;