rs753780877
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003922.4(HERC1):c.9748C>T(p.Arg3250Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
HERC1
NM_003922.4 stop_gained
NM_003922.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.14
Genes affected
HERC1 (HGNC:4867): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1) This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-63656210-G-A is Pathogenic according to our data. Variant chr15-63656210-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 188045.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC1 | NM_003922.4 | c.9748C>T | p.Arg3250Ter | stop_gained | 49/78 | ENST00000443617.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC1 | ENST00000443617.7 | c.9748C>T | p.Arg3250Ter | stop_gained | 49/78 | 1 | NM_003922.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247212Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134166
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460858Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726656
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Megalencephaly with thick corpus callosum, cerebellar atrophy, and intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular and pathophysiological bases of cognitive disorders, Institute Imagine | Feb 03, 2015 | - - |
Macrocephaly, dysmorphic facies, and psychomotor retardation Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 08, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at