rs7334118

Variant names:

• chr13-51939130-T-C
• rs7334118
• NM_000053.4:c.3620A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.3620A>G​(p.His1207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,212 control chromosomes in the GnomAD database, including 768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1207Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (122 hom., cov: 33)
  • Exomes 𝑓: 0.014 (646 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 3.46
• Publications: 23 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 -19 ACMG points.

• 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=0.0022899806).
• BP6: Variant 13-51939130-T-C is Benign according to our data. Variant chr13-51939130-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

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.3620A>G	p.His1207Arg	missense	Exon 17 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3620A>G	p.His1207Arg	missense	Exon 18 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3620A>G	p.His1207Arg	missense	Exon 18 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.3620A>G	p.His1207Arg	missense	Exon 17 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3476A>G	p.His1159Arg	missense	Exon 17 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3425A>G	p.His1142Arg	missense	Exon 16 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4153 AN: 152214 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00910

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0296 AC: 7396 AN: 249590 AF XY: 0.0244

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.000389

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00844

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0141 AC: 20647 AN: 1461880 Hom.: 646 Cov.: 32 AF XY: 0.0135 AC XY: 9805 AN XY: 727238

African (AFR) AF: 0.0483 AC: 1616 AN: 33480

American (AMR) AF: 0.141 AC: 6308 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 132 AN: 26136

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.0121 AC: 1046 AN: 86258

European-Finnish (FIN) AF: 0.00266 AC: 142 AN: 53410

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.00939 AC: 10442 AN: 1112008

Other (OTH) AF: 0.0148 AC: 893 AN: 60396

GnomAD4 genome AF: 0.0273 AC: 4162 AN: 152332 Hom.: 122 Cov.: 33 AF XY: 0.0277 AC XY: 2066 AN XY: 74498

African (AFR) AF: 0.0473 AC: 1968 AN: 41572

American (AMR) AF: 0.0930 AC: 1423 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68018

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0166 Hom.: 255

Bravo AF: 0.0360

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.0532 AC: 232

ESP6500EA AF: 0.00866 AC: 74

ExAC AF: 0.0257 AC: 3112

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	Wilson disease (11)
-	-	6	not specified (6)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0023	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	-1.2	N
PhyloP100		3.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.46
Sift	Benign	0.089	T
Sift4G	Benign	0.32	T
Polyphen		0.044	B
Vest4		0.14
MPC		0.094
ClinPred		0.061	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.79
Mutation Taster		=47/53	polymorphism (auto)

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: rs7334118; hg19: chr13-52513266;