chr19-18596711-C-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_004750.5(CRLF1):c.935G>T(p.Arg312Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,836 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004750.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRLF1 | NM_004750.5 | c.935G>T | p.Arg312Leu | missense_variant | 6/9 | ENST00000392386.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRLF1 | ENST00000392386.8 | c.935G>T | p.Arg312Leu | missense_variant | 6/9 | 1 | NM_004750.5 | P1 | |
CRLF1 | ENST00000684169.1 | c.935G>T | p.Arg312Leu | missense_variant | 6/9 | ||||
CRLF1 | ENST00000597131.1 | c.401G>T | p.Arg134Leu | missense_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250878Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135782
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461836Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727212
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cold-induced sweating syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Hacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of Medicine | Jun 01, 2020 | Sequencing analysis of the CRLF1 gene identified a novel homozygous missense variant (c.935G>T; p.Arg312Leu) in a patient whose clinical features were compatible with Crisponi syndrome. The R312L variant has not been reported in 1000 Genomes Project database and there is only one heterozygous individual in gnomAD data (allele frequency= 0.00000399). This variant was classified as likely pathogenic according to the ACMG guidelines and predicted to be deleterious by in silico pathogenicity prediction tools such as PolyPhen-2 and MutationTaster. Furthermore, alternative variants resulting in different amino acid substitutions at position 312 in CRLF1 have been associated with Crisponi syndrome (Piras et al., 2014). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at