chr13-51944145-G-T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP3_ModeratePP5_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 cumulative frequency of 0.000944 (AC=1,523) in the gnomAD database across 1,614,166 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.00143. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely 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. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.H1069L: Likely_pathogenic (ClinVar VariationId 2120118, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H1069= (synonymous): Likely_benign (ClinVar VariationId 2746502, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• 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:43 O:3
• Conservation: PhyloP100: 2.73
• Publications: 1 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, ClinGen, Orphanet, Natera, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00143 — borderline rare for AR gene (base 0.001, raised to 0.00322 by highest known P/LP ClinVar AF 0.00322) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.H1069L: Likely_pathogenic (ClinVar VariationId 2120118, 1 star); Other variants at the same amino acid residue (not pathogenic): p.H1069= (synonymous): Likely_benign (ClinVar VariationId 2746502, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (43/43 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated classification 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	Prot: NP_000044.2 UniProt:
	ATP7B NM_001406511.1		c.3207C>A p.His1069Gln	missense	Exon 15 of 22	Prot: NP_001393440.1 UniProt:
	ATP7B NM_001406512.1		c.3207C>A p.His1069Gln	missense	Exon 15 of 22	Prot: NP_001393441.1 UniProt:

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.3207C>Ap.His1069Gln

Exon rankExon 14 of 21

missense

Prot: NP_000044.2UniProt: P35670-1

ATP7B NM_001406511.1

HGVSc / HGVSpc.3207C>Ap.His1069Gln

Exon rankExon 15 of 22

missense

Prot: NP_001393440.1UniProt: P35670-1

ATP7B NM_001406512.1

HGVSc / HGVSpc.3207C>Ap.His1069Gln

Exon rankExon 15 of 22

missense

Prot: NP_001393441.1UniProt: P35670-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATP7B ENST00000242839.10	TSL:1MANE Select	c.3207C>A p.His1069Gln	missense	Exon 14 of 21	Prot: ENSP00000242839.5 UniProt:
	ATP7B ENST00000634844.1	TSL:1	c.3063C>A p.His1021Gln	missense	Exon 14 of 21	Prot: ENSP00000489398.1 UniProt:
	ATP7B ENST00000418097.7	TSL:1	c.3012C>A p.His1004Gln	missense	Exon 13 of 20	Prot: ENSP00000393343.2 UniProt:

ATP7B ENST00000242839.10

TSL:1MANE Select

HGVSc / HGVSpc.3207C>Ap.His1069Gln

Exon rankExon 14 of 21

missense

Prot: ENSP00000242839.5UniProt: P35670-1

ATP7B ENST00000634844.1

TSL:1

HGVSc / HGVSpc.3063C>Ap.His1021Gln

Exon rankExon 14 of 21

missense

Prot: ENSP00000489398.1UniProt: A0ACI8PQU0

ATP7B ENST00000418097.7

TSL:1

HGVSc / HGVSpc.3012C>Ap.His1004Gln

Exon rankExon 13 of 20

missense

Prot: ENSP00000393343.2UniProt: F5H748

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000933	AC:142	Hom:0	AN:152184	Cov:32
GnomAD2 exomes	AF: 0.000922	AC:230	Hom:	AN:249392	Cov:
GnomAD4 exome	AF: 0.000945	AC:1381	Hom:1	AN:1461864	Cov:31
GnomAD4 genome	AF: 0.000932	AC:142	Hom:0	AN:152302	Cov:32
TOPMed (Bravo)	AF: 0.000910	AC:241	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00126	AC:671	Hom:0	AN:534646	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000882	AC:11	Hom:	AN:12478	Cov:
Turkish Variome	AF: 0.000299	AC:2	Hom:0	AN:6682	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00126 *	14	11112	0.000908 *	16	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000844	24	28420	0.00128	37	28844
Epi25(Epilepsy)	0.00105	44	41958	0.00120	80	66886
SCHEMA(Schizophrenia)	0.000542	66	121786	0.000819	156	190524

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
32	-	-	Wilson disease (35)
10	-	-	not provided (10)
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
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
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.9	H
PhyloP100	Benign	2.7
popEVE	Benign	-3.7
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	N/A	0.95
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs76151636;

hg19: chr13-52518281;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar