NM_004750.5:c.1241G>T

Variant names:

• chr19-18594079-C-A
• NM_004750.5:c.1241G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004750.5(CRLF1):​c.1241G>T​(p.Arg414Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CRLF1 NM_004750.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.1241G>T	p.Arg414Leu	missense_variant	Exon 8 of 9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.1241G>T	p.Arg414Leu	missense_variant	Exon 8 of 9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.1246G>T	p.Gly416Trp	missense_variant	Exon 8 of 9			ENSP00000506849.1
CRLF1	ENST00000596360.1	n.56G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRLF1	ENST00000594325.1	n.189+168G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407714 Hom.: 0 Cov.: 43 AF XY: 0.00000144 AC XY: 1 AN XY: 695110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.27	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.39		Loss of MoRF binding (P = 0.0067);
MVP		0.90
MPC		0.47
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18704889;