rs137853932
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000392386.8(CRLF1):c.397+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000116 in 1,459,892 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
CRLF1
ENST00000392386.8 splice_donor
ENST00000392386.8 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.16
Genes affected
CRLF1 (HGNC:2364): (cytokine receptor like factor 1) This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells. Mutations in this gene result in Crisponi syndrome and cold-induced sweating syndrome. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2214342 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-18599564-C-T is Pathogenic according to our data. Variant chr19-18599564-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2504415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18599564-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CRLF1 | NM_004750.5 | c.397+1G>A | splice_donor_variant | ENST00000392386.8 | NP_004741.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRLF1 | ENST00000392386.8 | c.397+1G>A | splice_donor_variant | 1 | NM_004750.5 | ENSP00000376188 | P1 | |||
CRLF1 | ENST00000684169.1 | c.397+1G>A | splice_donor_variant | ENSP00000506849 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1459892Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726244
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31
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10
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726244
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2024 | Identified in an individual with CRLF1-related disorder, however segregation data and detailed clinical information were not provided (PMID: 24488861); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31497877, 24488861) - |
Cold-induced sweating syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Cone-rod dystrophy 12 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jun 22, 2023 | The homozygous pathogenic variant c.397+1G>A has been identified in a proband with features of arthrogryposis multiple congenita, global developmental delay. Failure to thrive, bilateral CTEV and knee & finger contractures. This variant is identified in intron 2 of CRLF1 gene where loss of function is a reported mechanism with 18 pathogenic variants. This variant is predicted to cause exon 2 skipping with 10% loss of transcript however, it does not alter the reading frame. Hence, the ACMG criteria of PVS1_strong is met. The variant has not been identified yet in gnomAD database (PM2_moderate). It has been previously reported (PP5_supporting) PMID 31497877. - |
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
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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_DG_spliceai
Position offset: -27
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at