NM_000053.4:c.3207C>T

Variant names:

• chr13-51944145-G-A
• rs76151636
• NM_000053.4:c.3207C>T
• ATP7B p.His1069His

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_ModerateBP7

The NM_000053.4(ATP7B):c.3207C>T (p.His1069His) variant causes a synonymous 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 (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.73
• Publications: 304 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: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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>T p.His1069His	synonymous	Exon 14 of 21	Prot: NP_000044.2 UniProt:
	ATP7B NM_001406511.1		c.3207C>T p.His1069His	synonymous	Exon 15 of 22	Prot: NP_001393440.1 UniProt:
	ATP7B NM_001406512.1		c.3207C>T p.His1069His	synonymous	Exon 15 of 22	Prot: NP_001393441.1 UniProt:

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.3207C>Tp.His1069His

Exon rankExon 14 of 21

synonymous

Prot: NP_000044.2UniProt: P35670-1

ATP7B NM_001406511.1

HGVSc / HGVSpc.3207C>Tp.His1069His

Exon rankExon 15 of 22

synonymous

Prot: NP_001393440.1UniProt: P35670-1

ATP7B NM_001406512.1

HGVSc / HGVSpc.3207C>Tp.His1069His

Exon rankExon 15 of 22

synonymous

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>T p.His1069His	synonymous	Exon 14 of 21	Prot: ENSP00000242839.5 UniProt:
	ATP7B ENST00000634844.1	TSL:1	c.3063C>T p.His1021His	synonymous	Exon 14 of 21	Prot: ENSP00000489398.1 UniProt:
	ATP7B ENST00000418097.7	TSL:1	c.3012C>T p.His1004His	synonymous	Exon 13 of 20	Prot: ENSP00000393343.2 UniProt:

ATP7B ENST00000242839.10

TSL:1MANE Select

HGVSc / HGVSpc.3207C>Tp.His1069His

Exon rankExon 14 of 21

synonymous

Prot: ENSP00000242839.5UniProt: P35670-1

ATP7B ENST00000634844.1

TSL:1

HGVSc / HGVSpc.3063C>Tp.His1021His

Exon rankExon 14 of 21

synonymous

Prot: ENSP00000489398.1UniProt: A0ACI8PQU0

ATP7B ENST00000418097.7

TSL:1

HGVSc / HGVSpc.3012C>Tp.His1004His

Exon rankExon 13 of 20

synonymous

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249392	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:534646	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Wilson disease (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.0
DANN	Benign	0.50
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
PhyloP100	Benign	2.7
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8

Showing 9 of 9 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