rs1801248

Variant names:

• chr13-51946299-C-T
• rs1801248
• NM_000053.4:c.3045G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000053.4(ATP7B):​c.3045G>A​(p.Leu1015Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,592,588 control chromosomes in the GnomAD database, including 1,103 homozygotes. In-silico tool predicts 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. L1015L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (74 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1029 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:19
• Conservation: PhyloP100: 0.602
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 13-51946299-C-T is Benign according to our data. Variant chr13-51946299-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35716.
• BP7: Synonymous conserved (PhyloP=0.602 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0255 (3878/152368) while in subpopulation NFE AF = 0.04 (2724/68032). AF 95% confidence interval is 0.0388. There are 74 homozygotes in GnomAd4. There are 1835 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 74 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.3045G>A	p.Leu1015Leu	synonymous	Exon 13 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.3045G>A	p.Leu1015Leu	synonymous	Exon 14 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.3045G>A	p.Leu1015Leu	synonymous	Exon 14 of 22	NP_001393441.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.3045G>A	p.Leu1015Leu	synonymous	Exon 13 of 21	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.2901G>A	p.Leu967Leu	synonymous	Exon 13 of 21	ENSP00000489398.1
	ATP7B	ENST00000448424.7	TSL:1	c.2793G>A	p.Leu931Leu	synonymous	Exon 11 of 19	ENSP00000416738.3

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3881 AN: 152250 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0254 AC: 5471 AN: 215302 AF XY: 0.0256

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.000128

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0353 AC: 50859 AN: 1440220 Hom.: 1029 Cov.: 31 AF XY: 0.0345 AC XY: 24665 AN XY: 714636

African (AFR) AF: 0.00625 AC: 207 AN: 33110

American (AMR) AF: 0.0172 AC: 710 AN: 41302

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 798 AN: 25730

East Asian (EAS) AF: 0.0000772 AC: 3 AN: 38862

South Asian (SAS) AF: 0.0107 AC: 894 AN: 83748

European-Finnish (FIN) AF: 0.0258 AC: 1345 AN: 52048

Middle Eastern (MID) AF: 0.0504 AC: 215 AN: 4270

European-Non Finnish (NFE) AF: 0.0408 AC: 44929 AN: 1101710

Other (OTH) AF: 0.0296 AC: 1758 AN: 59440

GnomAD4 genome AF: 0.0255 AC: 3878 AN: 152368 Hom.: 74 Cov.: 33 AF XY: 0.0246 AC XY: 1835 AN XY: 74522

African (AFR) AF: 0.00712 AC: 296 AN: 41590

American (AMR) AF: 0.0208 AC: 318 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4826

European-Finnish (FIN) AF: 0.0248 AC: 264 AN: 10626

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0400 AC: 2724 AN: 68032

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0336 Hom.: 175

Bravo AF: 0.0251

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	10	Wilson disease (13)
-	-	8	not specified (8)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.8
DANN	Benign	0.75
PhyloP100		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801248; hg19: chr13-52520435;