ENST00000911501.1:c.-411A>G

Variant names:

• chr13-52012013-T-C
• rs1021025464
• ENST00000911501.1:c.-411A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The ENST00000911501.1(ATP7B):​c.-411A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 361,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000732048: "In vitro studies indicate that chr13:g.52,586,149T>C reduces ATP7B promoter activity, likely through disruption of a metal regulatory transcription factor 1 (MTF1) binding site."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ATP7B ENST00000911501.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 2.96
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000732048: "In vitro studies indicate that chr13:g.52,586,149T>C reduces ATP7B promoter activity, likely through disruption of a metal regulatory transcription factor 1 (MTF1) binding site."; SCV000952513: Experimental studies have shown that this variant affects ATP7B function (PMID: 24094725, 30087448).; SCV002766270: Functional analysis have demonstrated that c.-676A>G reduced promotor activity, however, this report does not allow convincing conclusions about the variant effect in vivo (Mukherjee_2014).; SCV005365714: Functional assessment using luciferase promoter-reporter assays indicate that this variant leads to a decrease in reporter expression (Mukherjee et al. 2014. PubMed ID: 24094725, Figure 2; Chen et al. 2018. PubMed ID: 30087448, Figure 2).
• PP5: Variant 13-52012013-T-C is Pathogenic according to our data. Variant chr13-52012013-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393099.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000911501.1. 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_001406511.1		c.-55+7A>G		splice_region intron	N/A	NP_001393440.1	P35670-1
	ATP7B	NM_001406513.1		c.-55+7A>G		splice_region intron	N/A	NP_001393442.1
	ATP7B	NM_001406521.1		c.-55+7A>G		splice_region intron	N/A	NP_001393450.1	B7ZLR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000911501.1		c.-411A>G		5_prime_UTR	Exon 1 of 22	ENSP00000581560.1
	ATP7B	ENST00000873569.1		c.-676A>G		5_prime_UTR	Exon 1 of 21	ENSP00000543628.1
	ATP7B	ENST00000713659.1		c.-676A>G		5_prime_UTR	Exon 1 of 17	ENSP00000518961.1	A0AAQ5BGP2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000272 AC: 57 AN: 209360 Hom.: 0 Cov.: 0 AF XY: 0.000348 AC XY: 39 AN XY: 111964

African (AFR) AF: 0.000172 AC: 1 AN: 5824

American (AMR) AF: 0.000122 AC: 1 AN: 8182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5712

East Asian (EAS) AF: 0.00116 AC: 11 AN: 9476

South Asian (SAS) AF: 0.00121 AC: 42 AN: 34752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 790

European-Non Finnish (NFE) AF: 0.00000811 AC: 1 AN: 123268

Other (OTH) AF: 0.0000899 AC: 1 AN: 11122

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74512

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	-	Wilson disease (5)
1	1	-	not provided (2)
1	-	-	ATP7B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.72
PhyloP100		3.0
PromoterAI		-0.015	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1021025464; hg19: chr13-52586149;