rs2277448

Variant names:

• chr13-52011412-G-T
• rs2277448
• NM_000053.4:c.-75C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-52011412-G-T
• chr13-52011412-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.-75C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,603,372 control chromosomes in the GnomAD database, including 365,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27561 hom., cov: 34)
  • Exomes 𝑓: 0.68 (337517 hom.)
• Consequence: ATP7B NM_000053.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.36
• Publications: 26 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=-0.77).
• BP6: Variant 13-52011412-G-T is Benign according to our data. Variant chr13-52011412-G-T is described in ClinVar as Benign. ClinVar VariationId is 312405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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.-75C>A		5_prime_UTR	Exon 1 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406514.1		c.-75C>A		5_prime_UTR	Exon 1 of 21	NP_001393443.1
	ATP7B	NM_001406515.1		c.-75C>A		5_prime_UTR	Exon 1 of 21	NP_001393444.1	P35670-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.-75C>A		5_prime_UTR	Exon 1 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000448424.7	TSL:1	c.-75C>A		5_prime_UTR	Exon 1 of 19	ENSP00000416738.3	E7ET55
	ATP7B	ENST00000873569.1		c.-75C>A		5_prime_UTR	Exon 1 of 21	ENSP00000543628.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87665 AN: 151958 Hom.: 27555 Cov.: 34

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.638

GnomAD4 exome AF: 0.678 AC: 983477 AN: 1451296 Hom.: 337517 Cov.: 28 AF XY: 0.675 AC XY: 487811 AN XY: 722498

African (AFR) AF: 0.289 AC: 9598 AN: 33154

American (AMR) AF: 0.660 AC: 29266 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 16525 AN: 26052

East Asian (EAS) AF: 0.564 AC: 22292 AN: 39552

South Asian (SAS) AF: 0.545 AC: 46793 AN: 85906

European-Finnish (FIN) AF: 0.700 AC: 37118 AN: 53006

Middle Eastern (MID) AF: 0.697 AC: 4009 AN: 5752

European-Non Finnish (NFE) AF: 0.705 AC: 778083 AN: 1103492

Other (OTH) AF: 0.663 AC: 39793 AN: 60056

GnomAD4 genome AF: 0.577 AC: 87687 AN: 152076 Hom.: 27561 Cov.: 34 AF XY: 0.578 AC XY: 42971 AN XY: 74336

African (AFR) AF: 0.304 AC: 12609 AN: 41478

American (AMR) AF: 0.646 AC: 9893 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2228 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3061 AN: 5144

South Asian (SAS) AF: 0.539 AC: 2602 AN: 4826

European-Finnish (FIN) AF: 0.705 AC: 7455 AN: 10570

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47788 AN: 67964

Other (OTH) AF: 0.640 AC: 1352 AN: 2114

Alfa AF: 0.605 Hom.: 15171

Bravo AF: 0.564

Asia WGS AF: 0.560 AC: 1945 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Wilson disease (5)
-	-	4	not specified (4)
-	-	1	Congenital disorder of glycosylation (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.1
DANN	Benign	0.47
PhyloP100		-1.4
PromoterAI		-0.0028	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2277448; hg19: chr13-52585548; COSMIC: COSV54445614; COSMIC: COSV54445614;