rs138427376

Variant names:

• chr13-51968544-A-G
• rs138427376
• NM_000053.4:c.1607T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-51968544-A-G
• chr13-51968544-A-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_000053.4(ATP7B):​c.1607T>C​(p.Val536Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,854 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. V536F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:13 O:1
• Conservation: PhyloP100: 1.25
• Publications: 14 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 -6 ACMG points.

• PM1: In a hotspot region, there are 3 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=0.012235105).
• BP6: Variant 13-51968544-A-G is Benign according to our data. Variant chr13-51968544-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35703.
• 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.1607T>C	p.Val536Ala	missense	Exon 4 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.1607T>C	p.Val536Ala	missense	Exon 5 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.1607T>C	p.Val536Ala	missense	Exon 5 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.1607T>C	p.Val536Ala	missense	Exon 4 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.1607T>C	p.Val536Ala	missense	Exon 4 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.1607T>C	p.Val536Ala	missense	Exon 4 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 498 AN: 151848 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00465

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00319 AC: 797 AN: 249456 AF XY: 0.00328

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00455 AC: 6651 AN: 1461888 Hom.: 23 Cov.: 32 AF XY: 0.00436 AC XY: 3173 AN XY: 727244

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.0107 AC: 571 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00518 AC: 5762 AN: 1112008

Other (OTH) AF: 0.00381 AC: 230 AN: 60396

GnomAD4 genome AF: 0.00328 AC: 498 AN: 151966 Hom.: 2 Cov.: 32 AF XY: 0.00369 AC XY: 274 AN XY: 74286

African (AFR) AF: 0.000941 AC: 39 AN: 41442

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00465 AC: 316 AN: 67938

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00361 Hom.: 2

Bravo AF: 0.00239

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000474 AC: 2

ESP6500EA AF: 0.00309 AC: 26

ExAC AF: 0.00298 AC: 361

EpiCase AF: 0.00387

EpiControl AF: 0.00456

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	Wilson disease (9)
-	-	5	not provided (5)
-	1	1	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	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.56
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.94
MPC		0.070
ClinPred		0.0072	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.33
Mutation Taster		=91/9	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: rs138427376; hg19: chr13-52542680;