NM_004750.5:c.*11C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0540

Publications

1 publications found

Variant links:

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]

CRLF1 Gene-Disease associations (from GenCC):

Cold-induced sweating syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cold-induced sweating syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
idiopathic achalasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CRLF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.*11C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000392386.8	NP_004741.1	O75462

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRLF1	ENST00000392386.8 link	c.*11C>A	3_prime_UTR_variant	Exon 9 of 9	1	NM_004750.5	ENSP00000376188.2	O75462
CRLF1	ENST00000596360.1 link	n.95C>A	non_coding_transcript_exon_variant	Exon 2 of 2	2
CRLF1	ENST00000684169.1 link	c.*4C>A	3_prime_UTR_variant	Exon 9 of 9			ENSP00000506849.1	A0A804HI12
CRLF1	ENST00000594325.1 link	n.189+692C>A	intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

354

AN:

152244

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00372

AC XY:

2699

AN XY:

725132

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33450

American (AMR)

AF:

0.000789

AC:

AN:

44332

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.000129

AC:

AN:

85532

European-Finnish (FIN)

AF:

0.00149

AC:

AN:

52352

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00475

AC:

5273

AN:

1110902

Other (OTH)

AF:

0.00256

AC:

154

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

308

615

923

1230

1538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152362

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41592

American (AMR)

AF:

0.00105

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00422

AC:

287

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00235

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

(source)

DANN

Benign

0.71

PhyloP100

-0.054

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_004750.5:c.*11C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over