rs141414233
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_003922.4(HERC1):c.6225+4C>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 0.0073 in 1,581,242 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0054 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0075 ( 43 hom. )
Consequence
HERC1
NM_003922.4 splice_donor_region, intron
NM_003922.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00009236
2
Clinical Significance
Conservation
PhyloP100: -4.30
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.99).
BP6
Variant 15-63686355-G-A is Benign according to our data. Variant chr15-63686355-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63686355-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00544 (827/152024) while in subpopulation NFE AF= 0.00957 (651/67992). AF 95% confidence interval is 0.00897. There are 1 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 43 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HERC1 | NM_003922.4 | c.6225+4C>T | splice_donor_region_variant, intron_variant | ENST00000443617.7 | NP_003913.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HERC1 | ENST00000443617.7 | c.6225+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_003922.4 | ENSP00000390158 | P1 | |||
ENST00000559303.2 | n.287+8036G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00544 AC: 827AN: 151908Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00527 AC: 1182AN: 224164Hom.: 5 AF XY: 0.00534 AC XY: 651AN XY: 121810
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GnomAD4 exome AF: 0.00750 AC: 10722AN: 1429218Hom.: 43 Cov.: 29 AF XY: 0.00736 AC XY: 5227AN XY: 710032
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GnomAD4 genome AF: 0.00544 AC: 827AN: 152024Hom.: 1 Cov.: 32 AF XY: 0.00486 AC XY: 361AN XY: 74282
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | HERC1: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 27, 2016 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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