NM_000053.4:c.3101A>G

Variant names:

• chr13-51944251-T-C
• rs74085882
• NM_000053.4:c.3101A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000053.4(ATP7B):​c.3101A>G​(p.His1034Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,040 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 2.77
• Publications: 5 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 -17 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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=0.018963426).
• BP6: Variant 13-51944251-T-C is Benign according to our data. Variant chr13-51944251-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00395 (601/152210) while in subpopulation AFR AF = 0.0141 (584/41536). AF 95% confidence interval is 0.0131. There are 3 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.3101A>G	p.His1034Arg	missense	Exon 14 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3101A>G	p.His1034Arg	missense	Exon 15 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3101A>G	p.His1034Arg	missense	Exon 15 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.3101A>G	p.His1034Arg	missense	Exon 14 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2957A>G	p.His986Arg	missense	Exon 14 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2906A>G	p.His969Arg	missense	Exon 13 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152092 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000961 AC: 239 AN: 248676 AF XY: 0.000681

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000335 AC: 489 AN: 1461830 Hom.: 3 Cov.: 31 AF XY: 0.000263 AC XY: 191 AN XY: 727210

African (AFR) AF: 0.0115 AC: 384 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112008

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152210 Hom.: 3 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74430

African (AFR) AF: 0.0141 AC: 584 AN: 41536

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00130 Hom.: 5

Bravo AF: 0.00442

ESP6500AA AF: 0.0110 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 141

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	-1.0	N
PhyloP100		2.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.37
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.072	B
Vest4		0.33
MVP		0.95
MPC		0.22
ClinPred		0.064	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.68
Mutation Taster		=33/67	disease causing

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: rs74085882; hg19: chr13-52518387;