rs140316223
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_018063.5(HELLS):c.370+2T>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000977 in 1,432,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000098 ( 0 hom. )
Consequence
HELLS
NM_018063.5 splice_donor
NM_018063.5 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.00
Genes affected
HELLS (HGNC:4861): (helicase, lymphoid specific) This gene encodes a lymphoid-specific helicase. Other helicases function in processes involving DNA strand separation, including replication, repair, recombination, and transcription. This protein is thought to be involved with cellular proliferation and may play a role in leukemogenesis. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.014302742 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -36, new splice context is: aggGTaaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 10-94562729-T-A is Pathogenic according to our data. Variant chr10-94562729-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 225524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-94562729-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HELLS | NM_018063.5 | c.370+2T>A | splice_donor_variant | ENST00000348459.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HELLS | ENST00000348459.10 | c.370+2T>A | splice_donor_variant | 1 | NM_018063.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.00000826 AC: 2AN: 242268Hom.: 0 AF XY: 0.00000765 AC XY: 1AN XY: 130706
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GnomAD4 exome AF: 0.00000977 AC: 14AN: 1432410Hom.: 0 Cov.: 27 AF XY: 0.00000561 AC XY: 4AN XY: 713312
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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
Immunodeficiency-centromeric instability-facial anomalies syndrome 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 21, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2023 | ClinVar contains an entry for this variant (Variation ID: 225524). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 26216346). The resulting mRNA is expected to undergo nonsense-mediated decay. Disruption of this splice site has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 26216346). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs140316223, gnomAD 0.002%). This sequence change affects a donor splice site in intron 5 of the HELLS gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at