rs137853927

Positions:

• chr19-18596895-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5

The ENST00000392386.8(CRLF1):​c.852G>T​(p.Trp284Cys) variant causes a missense 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 Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRLF1 ENST00000392386.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.07

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.

• PS1: Transcript ENST00000392386.8 (CRLF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 ENST00000392386.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 19-18596895-C-A is Pathogenic according to our data. Variant chr19-18596895-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.852G>T	p.Trp284Cys	missense_variant	5/9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.852G>T	p.Trp284Cys	missense_variant	5/9	1	NM_004750.5	ENSP00000376188	P1
CRLF1	ENST00000684169.1	c.852G>T	p.Trp284Cys	missense_variant	5/9			ENSP00000506849
CRLF1	ENST00000597131.1	c.318G>T	p.Trp106Cys	missense_variant	2/4	2		ENSP00000470625

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	37
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.86		Gain of methylation at K285 (P = 0.0208);
MVP		0.83
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853927; hg19: chr19-18707705;