rs34503316

Positions:

• chr19-18606579-GAGC-G
• chr19-18606579-GAGC-GAGCAGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004750.5(CRLF1):​c.75_77delGCT​(p.Leu26del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,139,378 control chromosomes in the GnomAD database, including 26,591 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3707 hom., cov: 21)
  • Exomes 𝑓: 0.21 (22884 hom.)
• Consequence: CRLF1 NM_004750.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.814

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-18606579-GAGC-G is Benign according to our data. Variant chr19-18606579-GAGC-G is described in ClinVar as [Benign]. Clinvar id is 224611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18606579-GAGC-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	1/9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	1/9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	1/9			ENSP00000506849.1
CRLF1	ENST00000593286.1	n.367+793_367+795delGCT		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.212 AC: 31311 AN: 147948 Hom.: 3692 Cov.: 21

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.219

GnomAD3 exomes AF: 0.0917 AC: 11 AN: 120 Hom.: 0 AF XY: 0.0641 AC XY: 5 AN XY: 78

Gnomad AFR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.208 AC: 206190 AN: 991362 Hom.: 22884 AF XY: 0.207 AC XY: 96502 AN XY: 466382

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.0985

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.212 AC: 31343 AN: 148016 Hom.: 3707 Cov.: 21 AF XY: 0.215 AC XY: 15489 AN XY: 72188

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.489

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.214

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.227

Alfa AF: 0.119 Hom.: 192

Bravo AF: 0.223

Asia WGS AF: 0.353 AC: 1165 AN: 3316

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2024	Variant summary: CRLF1 c.75_77delGCT (p.Leu26del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.21 in 1139378 control chromosomes, predominantly at a frequency of 0.5 within the Non-Finnish European subpopulation in the gnomAD database, including 2931 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 458.83 fold of the estimated maximal expected allele frequency for a pathogenic variant in CRLF1 causing Cold-Induced Sweating Syndrome phenotype (0.0011). To our knowledge, no occurrence of c.75_77delGCT in individuals affected with Cold-Induced Sweating Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 224611). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs34503316; hg19: chr19-18717389;