NM_000053.4:c.3688A>G

Variant names:

• chr13-51939062-T-C
• rs200911496
• NM_000053.4:c.3688A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM5 PP2 PP5 BS2_Supporting

The NM_000053.4(ATP7B):​c.3688A>G​(p.Ile1230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,614,256 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1230L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:12
• Conservation: PhyloP100: 7.97
• 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, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51939062-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1497544.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• PP5: Variant 13-51939062-T-C is Pathogenic according to our data. Variant chr13-51939062-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 312379.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3688A>G	p.Ile1230Val	missense	Exon 17 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.3688A>G	p.Ile1230Val	missense	Exon 18 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.3688A>G	p.Ile1230Val	missense	Exon 18 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.3688A>G	p.Ile1230Val	missense	Exon 17 of 21	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.3544A>G	p.Ile1182Val	missense	Exon 17 of 21	ENSP00000489398.1
	ATP7B	ENST00000418097.7	TSL:1	c.3493A>G	p.Ile1165Val	missense	Exon 16 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000321 AC: 80 AN: 249584 AF XY: 0.000362

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000600

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000675 AC: 987 AN: 1461890 Hom.: 2 Cov.: 32 AF XY: 0.000671 AC XY: 488 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000834 AC: 927 AN: 1112008

Other (OTH) AF: 0.000679 AC: 41 AN: 60396

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74512

African (AFR) AF: 0.000216 AC: 9 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000473 AC: 4

ExAC AF: 0.000297 AC: 36

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	6	-	Wilson disease (13)
-	3	-	not provided (3)
-	2	-	not specified (2)
1	-	-	ATP7B-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.66	N
PhyloP100		8.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.81	N
REVEL	Pathogenic	0.80
Sift	Benign	0.055	T
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.74
MVP		0.84
MPC		0.35
ClinPred		0.077	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.67
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200911496; hg19: chr13-52513198; COSMIC: COSV105028204; COSMIC: COSV105028204;