rs770829226

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000242839.10(ATP7B):​c.1708-5T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATP7B
ENST00000242839.10 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.1728
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.55
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-51965038-A-C is Pathogenic according to our data. Variant chr13-51965038-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7BNM_000053.4 linkuse as main transcriptc.1708-5T>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000242839.10 NP_000044.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkuse as main transcriptc.1708-5T>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_000053.4 ENSP00000242839 P1P35670-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249466
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135372
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461786
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:6
Pathogenic, no assertion criteria providedclinical testingCounsylApr 06, 2017- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2022For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 495402). This variant has been observed in individual(s) with Wilson disease (PMID: 8526905, 11721763, 21707886, 28507923). This variant is present in population databases (rs770829226, gnomAD 0.01%). This sequence change falls in intron 4 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 07, 2024- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 30, 2016Variant summary: The ATP7B c.1708-5T>G variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict an affect on splicing. A functional study, Shimizu_1995 supports these predictions with the observation of the variant causing exon 5 skipping. The variant of interest was observed in controls with an allele frequency of 1/120756, which does not exceed the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/185. Multiple publications report the variant in Wilson Disease patients as homozygotes and compound heterozygotes, predominantly in Japanese individuals. Multiple databases have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
19
DANN
Benign
0.66
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.17
dbscSNV1_RF
Benign
0.45
SpliceAI score (max)
0.64
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.45
Position offset: 44
DS_AL_spliceai
0.64
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770829226; hg19: chr13-52539174; API