19-18594357-T-A

Position:

• chr19-18594357-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004750.5(CRLF1):​c.1102A>T​(p.Lys368Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CRLF1 NM_004750.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-18594357-T-A is Pathogenic according to our data. Variant chr19-18594357-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 5711.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-18594357-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF1	NM_004750.5	c.1102A>T	p.Lys368Ter	stop_gained	7/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF1	ENST00000392386.8	c.1102A>T	p.Lys368Ter	stop_gained	7/9	1	NM_004750.5	P1
CRLF1	ENST00000684169.1	c.1102A>T	p.Lys368Ter	stop_gained	7/9
CRLF1	ENST00000594325.1	n.79A>T		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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cold-induced sweating syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2007

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.60	D
MutationTaster	Benign	1.0	A
Vest4		0.82
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs137853144; hg19: chr19-18705167;