NM_000053.4:c.2355+13T>G

Variant names:

• chr13-51958298-A-C
• rs139211339
• NM_000053.4:c.2355+13T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000053.4(ATP7B):​c.2355+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,232 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (8 hom.)
• Consequence: ATP7B NM_000053.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• Conservation: PhyloP100: -0.104
• 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, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-51958298-A-C is Benign according to our data. Variant chr13-51958298-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157938.
• 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.2355+13T>G		intron	N/A	NP_000044.2
	ATP7B	NM_001406511.1		c.2355+13T>G		intron	N/A	NP_001393440.1
	ATP7B	NM_001406512.1		c.2355+13T>G		intron	N/A	NP_001393441.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2355+13T>G		intron	N/A	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.2211+13T>G		intron	N/A	ENSP00000489398.1
	ATP7B	ENST00000418097.7	TSL:1	c.2355+13T>G		intron	N/A	ENSP00000393343.2

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00288 AC: 717 AN: 248902 AF XY: 0.00287

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00617

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00339 AC: 4947 AN: 1460926 Hom.: 8 Cov.: 30 AF XY: 0.00327 AC XY: 2380 AN XY: 726836

African (AFR) AF: 0.000508 AC: 17 AN: 33458

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86222

European-Finnish (FIN) AF: 0.00563 AC: 301 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00384 AC: 4272 AN: 1111148

Other (OTH) AF: 0.00277 AC: 167 AN: 60376

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74478

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10620

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00420 AC: 286 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00405 Hom.: 2

Bravo AF: 0.00204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	4	Wilson disease (5)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.45
DANN	Benign	0.62
PhyloP100		-0.10
Mutation Taster		=100/0	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: rs139211339; hg19: chr13-52532434;