19-18594338-A-C

Position:

• chr19-18594338-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004750.5(CRLF1):​c.1121T>G​(p.Leu374Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: CRLF1 NM_004750.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF1	NM_004750.5	c.1121T>G	p.Leu374Arg	missense_variant	7/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF1	ENST00000392386.8	c.1121T>G	p.Leu374Arg	missense_variant	7/9	1	NM_004750.5	P1
CRLF1	ENST00000684169.1	c.1121T>G	p.Leu374Arg	missense_variant	7/9
CRLF1	ENST00000594325.1	n.98T>G		non_coding_transcript_exon_variant	1/3	3
CRLF1	ENST00000597131.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 29

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Cold-induced sweating syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Persons of Israeli ancestry reported as homozygous for both variants c.242G>A and c.1121T>G -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.68	A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.84	P
Vest4		0.32
MutPred		0.80		Gain of sheet (P = 0.0011);
MVP		0.86
MPC		0.92
ClinPred		0.91	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs104894668; hg19: chr19-18705148;