19-18593555-G-T

Variant names:

• chr19-18593555-G-T
• rs140234226
• NM_004750.5:c.*11C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004750.5(CRLF1):​c.*11C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,610,604 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (18 hom.)
• Consequence: CRLF1 NM_004750.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0540

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-18593555-G-T is Benign according to our data. Variant chr19-18593555-G-T is described in ClinVar as [Benign]. Clinvar id is 3907392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00232 (354/152362) while in subpopulation NFE AF = 0.00422 (287/68034). AF 95% confidence interval is 0.00382. There are 0 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.*11C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.*11C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.*4C>A		3_prime_UTR_variant	Exon 9 of 9			ENSP00000506849.1
CRLF1	ENST00000596360.1	n.95C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
CRLF1	ENST00000594325.1	n.189+692C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00240 AC: 574 AN: 239348 AF XY: 0.00249

Gnomad AFR exome AF: 0.000786

Gnomad AMR exome AF: 0.000737

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.00463

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00384 AC: 5597 AN: 1458242 Hom.: 18 Cov.: 31 AF XY: 0.00372 AC XY: 2699 AN XY: 725132

African (AFR) AF: 0.000508 AC: 17 AN: 33450

American (AMR) AF: 0.000789 AC: 35 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85532

European-Finnish (FIN) AF: 0.00149 AC: 78 AN: 52352

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5762

European-Non Finnish (NFE) AF: 0.00475 AC: 5273 AN: 1110902

Other (OTH) AF: 0.00256 AC: 154 AN: 60224

GnomAD4 genome AF: 0.00232 AC: 354 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74500

African (AFR) AF: 0.000890 AC: 37 AN: 41592

American (AMR) AF: 0.00105 AC: 16 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 04, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CRLF1 c.*11C>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0024 in 239348 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CRLF1 causing Cold-induced sweating syndrome 1 phenotype (0.0011). To our knowledge, no occurrence of c.*11C>A in individuals affected with Cold-induced sweating syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.3
DANN	Benign	0.71
PhyloP100		-0.054
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs140234226; hg19: chr19-18704365;