rs368315540
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_003922.4(HERC1):c.3021+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,611,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
HERC1
NM_003922.4 splice_donor_region, intron
NM_003922.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00002257
2
Clinical Significance
Conservation
PhyloP100: 0.879
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
?
Variant 15-63729491-G-A is Benign according to our data. Variant chr15-63729491-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547868.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000592 (9/152076) while in subpopulation NFE AF= 0.000118 (8/68012). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC1 | NM_003922.4 | c.3021+6C>T | splice_donor_region_variant, intron_variant | ENST00000443617.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC1 | ENST00000443617.7 | c.3021+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_003922.4 | P1 | |||
HERC1 | ENST00000561400.1 | c.931-13018C>T | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152076Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
9
AN:
152076
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248564Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134818
GnomAD3 exomes
AF:
AC:
6
AN:
248564
Hom.:
AF XY:
AC XY:
0
AN XY:
134818
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000295 AC: 43AN: 1459330Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19AN XY: 725512
GnomAD4 exome
AF:
AC:
43
AN:
1459330
Hom.:
Cov.:
31
AF XY:
AC XY:
19
AN XY:
725512
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152076Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74292
GnomAD4 genome
?
AF:
AC:
9
AN:
152076
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
74292
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Macrocephaly, dysmorphic facies, and psychomotor retardation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 12, 2016 | - - |
HERC1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 20, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at