19-18594079-C-T

Variant names:

• chr19-18594079-C-T
• rs1555757514
• NM_004750.5:c.1241G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004750.5(CRLF1):​c.1241G>A​(p.Arg414Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000568 in 1,407,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CRLF1 NM_004750.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39549586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.1241G>A	p.Arg414Gln	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>A	p.Arg414Gln	missense_variant	Exon 8 of 9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.1246G>A	p.Gly416Arg	missense_variant	Exon 8 of 9			ENSP00000506849.1
CRLF1	ENST00000596360.1	n.56G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRLF1	ENST00000594325.1	n.189+168G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000178 AC: 3 AN: 168460 Hom.: 0 AF XY: 0.0000222 AC XY: 2 AN XY: 90122

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: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000568 AC: 8 AN: 1407714 Hom.: 0 Cov.: 43 AF XY: 0.0000101 AC XY: 7 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: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000553

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1241G>A (p.R414Q) alteration is located in exon 8 (coding exon 8) of the CRLF1 gene. This alteration results from a G to A substitution at nucleotide position 1241, causing the arginine (R) at amino acid position 414 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.10	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.50
MutPred		0.32		Loss of methylation at R414 (P = 0.0136);
MVP		0.87
MPC		0.48
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555757514; hg19: chr19-18704889;