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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 missense

Scores

12
6
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.35
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a domain Fibronectin type-III 2 (size 104) in uniprot entity CRLF1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_004750.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 19-18596711-C-A is Pathogenic according to our data. Variant chr19-18596711-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929437.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRLF1NM_004750.5 linkuse as main transcriptc.935G>T p.Arg312Leu missense_variant 6/9 ENST00000392386.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRLF1ENST00000392386.8 linkuse as main transcriptc.935G>T p.Arg312Leu missense_variant 6/91 NM_004750.5 P1
CRLF1ENST00000684169.1 linkuse as main transcriptc.935G>T p.Arg312Leu missense_variant 6/9
CRLF1ENST00000597131.1 linkuse as main transcriptc.401G>T p.Arg134Leu missense_variant 3/42

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250878
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461836
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cold-induced sweating syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingHacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of MedicineJun 01, 2020Sequencing 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Pathogenic
3.5
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.77
MutPred
0.79
Loss of MoRF binding (P = 0.0858);
MVP
0.95
MPC
1.3
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.83
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137853933; hg19: chr19-18707521; API