13-51944145-G-T

Variant names:

• chr13-51944145-G-T
• rs76151636
• NM_000053.4:c.3207C>A
• ATP7B p.His1069Gln

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3207C>A​(p.His1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000052016: The most pronounced variant effect results in <10% of normal nucleotide binding activity (e.g., Morgan_2004). PMID:17717039, 10544227, 11690702, 15205462, 24897373, 21334398" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1069R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:40 O:3
• Conservation: PhyloP100: 2.73
• Publications: 308 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052016: The most pronounced variant effect results in <10% of normal nucleotide binding activity (e.g., Morgan_2004). PMID: 17717039, 10544227, 11690702, 15205462, 24897373, 21334398; SCV000602583: Functional studies indicate that the variant protein has altered subcellular localization (Payne 1998, van den Berghe 2009), reduced affinity to ATP (Morgan 2004, Rodriguez-Granillo 2008) and reduced half-life (Payne 1998). Cells expressing the variant protein show reduced viability when exposed to increased levels of copper (Payne 1998). PMID: 9724794; SCV000626851: Experimental studies have shown that this missense change affects ATP7B function (PMID: 9724794, 19937698, 22240481, 24909901).; SCV000967653: "In vitro functional studies provide some evidence that the p.His1069Gln variant may result in reduced ATP7B protein expression (van den Berghe 2009)"; SCV001142439: Functional studies demonstrate that p.His1069Gln had a very low activity compared to wildtype (PMID: 22240481), resulted in reduced ATP7B protein expression (PMID: 19937698), and caused subcellular mislocalization (PMID: 24909901).; SCV002051776: Functional studies demonstrate that this substitution results in mislocalization and increased degradation of the ATP7B protein in cells.; SCV002767518: Functional studies of mutant protein disrupts intracellar copper balance and reduced protein stability (Huster D. et al. (2003), Rodriguez-Granillo, A., et al. (2008)).; SCV003920292: In vivo and In vitro functional studies suggest that this variant reduces ATP binding and is retained in the endoplasmic reticulum (Morgan 2004 PMID:15205462, Mercer 2017 PMID:28119449, Parisi 2018 PMID:29674751).; SCV004361971: Functional studies have shown that this variant results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388).; SCV004845404: Functional studies have shown that this variant results in reduced ATP7B protein expression, subcellular mislocalization of the ATP7B protein to the endoplasmic reticulum where it undergoes rapid degradation, and partial loss of copper export activity (PMID: 8298641, 9654149, 9724794, 10051024, 12557139, 17717039, 18692069, 19937698, 21398519, 22240481, 22692182, 24253677, 24909901, 28119449, 29674751, 30026388).; SCV000329091: Published functional studies show the H1069Q variant has significantly reduced ATP binding affinity and reduced protein stability, leading to impaired copper transport (Dmitriev et al., 2011; Morgan et al., 2004; Rodriguez-Granillo et al., 2008; Chesi et al., 2016);; SCV001247795: PS3:Moderate; SCV004026153: PS3; SCV002610410: Based on several functional studies, this mutation affects ATP binding, protein dynamics, and chemical and thermal stabilities relative to wild type (Rodriguez-Granillo, 2008; Dmitriev, 2011; Morgan, 2004).
• PM1: In a hotspot region, there are 11 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 chr13-51944146-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1069926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 13-51944145-G-T is Pathogenic according to our data. Variant chr13-51944145-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3207C>A	p.His1069Gln	missense	Exon 14 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3207C>A	p.His1069Gln	missense	Exon 15 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3207C>A	p.His1069Gln	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.3207C>A	p.His1069Gln	missense	Exon 14 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3063C>A	p.His1021Gln	missense	Exon 14 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3012C>A	p.His1004Gln	missense	Exon 13 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000922 AC: 230 AN: 249392 AF XY: 0.000850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000945 AC: 1381 AN: 1461864 Hom.: 1 Cov.: 31 AF XY: 0.000956 AC XY: 695 AN XY: 727226

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

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 143 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00102 AC: 1135 AN: 1112010

Other (OTH) AF: 0.000944 AC: 57 AN: 60394

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74464

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68020

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

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.000910

EpiCase AF: 0.00104

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
30	-	-	Wilson disease (33)
9	-	-	not provided (9)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.95
gMVP		0.92
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs76151636;

hg19: chr13-52518281;