13-51944145-G-C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5PP3_Moderate

The NM_000053.4(ATP7B):c.3207C>G (p.His1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: not found (cov: 32)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 12 pathogenic, 0 benign (OR vs. background: 125.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.00322 by highest known P/LP ClinVar AF 0.00322) — PM2 moderate.
	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).

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>G p.His1069Gln	missense	Exon 14 of 21	Prot: NP_000044.2 UniProt:
	ATP7B NM_001406511.1		c.3207C>G p.His1069Gln	missense	Exon 15 of 22	Prot: NP_001393440.1 UniProt:
	ATP7B NM_001406512.1		c.3207C>G p.His1069Gln	missense	Exon 15 of 22	Prot: NP_001393441.1 UniProt:

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.3207C>Gp.His1069Gln

Exon rankExon 14 of 21

missense

Prot: NP_000044.2UniProt: P35670-1

ATP7B NM_001406511.1

HGVSc / HGVSpc.3207C>Gp.His1069Gln

Exon rankExon 15 of 22

missense

Prot: NP_001393440.1UniProt: P35670-1

ATP7B NM_001406512.1

HGVSc / HGVSpc.3207C>Gp.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>G p.His1069Gln	missense	Exon 14 of 21	Prot: ENSP00000242839.5 UniProt:
	ATP7B ENST00000634844.1	TSL:1	c.3063C>G p.His1021Gln	missense	Exon 14 of 21	Prot: ENSP00000489398.1 UniProt:
	ATP7B ENST00000418097.7	TSL:1	c.3012C>G p.His1004Gln	missense	Exon 13 of 20	Prot: ENSP00000393343.2 UniProt:

ATP7B ENST00000242839.10

TSL:1MANE Select

HGVSc / HGVSpc.3207C>Gp.His1069Gln

Exon rankExon 14 of 21

missense

Prot: ENSP00000242839.5UniProt: P35670-1

ATP7B ENST00000634844.1

TSL:1

HGVSc / HGVSpc.3063C>Gp.His1021Gln

Exon rankExon 14 of 21

missense

Prot: ENSP00000489398.1UniProt: A0ACI8PQU0

ATP7B ENST00000418097.7

TSL:1

HGVSc / HGVSpc.3012C>Gp.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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	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	0.93	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	0/100	disease causing
MutationAssessor	Pathogenic	3.9	H
PhyloP100	Benign	2.7
popEVE	Benign	-3.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.5	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8
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 30 of 30 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

hg19: chr13-52518281;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar