rs72552259

Variant names:

• chr13-51960274-C-T
• rs72552259
• NM_000053.4:c.1995G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Strong BS2

The NM_000053.4(ATP7B):​c.1995G>A​(p.Met665Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,894 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M665V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18 B:2
• Conservation: PhyloP100: 2.43
• Publications: 20 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000053.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011927754).
• BS2: High Homozygotes in GnomAd4 at 2 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.1995G>A	p.Met665Ile	missense	Exon 7 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.1995G>A	p.Met665Ile	missense	Exon 8 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.1995G>A	p.Met665Ile	missense	Exon 8 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.1995G>A	p.Met665Ile	missense	Exon 7 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.1995G>A	p.Met665Ile	missense	Exon 7 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.1995G>A	p.Met665Ile	missense	Exon 7 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00150 AC: 374 AN: 249208 AF XY: 0.00169

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00211 AC: 3090 AN: 1461594 Hom.: 10 Cov.: 31 AF XY: 0.00221 AC XY: 1605 AN XY: 727102

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.000850 AC: 38 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 164 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00204 AC: 176 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000875 AC: 5 AN: 5712

European-Non Finnish (NFE) AF: 0.00229 AC: 2544 AN: 1111840

Other (OTH) AF: 0.00252 AC: 152 AN: 60370

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74458

African (AFR) AF: 0.000409 AC: 17 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00142

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.00263 AC: 22

ExAC AF: 0.00132 AC: 160

EpiCase AF: 0.00213

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	12	1	Wilson disease (13)
-	3	1	not provided (4)
-	1	-	Epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.0078
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.021	D
Sift4G	Benign	0.062	T
Polyphen		0.17	B
Vest4		0.39
MutPred		0.81		Gain of helix (P = 0.0854)
MVP		0.93
MPC		0.066
ClinPred		0.016	T
GERP RS		4.5
Varity_R		0.38
gMVP		0.83
Mutation Taster		=73/27	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: rs72552259; hg19: chr13-52534410;