rs34503316

Variant names:

• chr19-18606579-GAGC-G
• rs34503316
• NM_004750.5:c.75_77delGCT

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• cold-induced sweating syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 224611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004750.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF1	NM_004750.5	MANE Select	c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	Exon 1 of 9	NP_004741.1	O75462

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF1	ENST00000392386.8	TSL:1 MANE Select	c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000376188.2	O75462
	CRLF1	ENST00000928241.1		c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000598300.1
	CRLF1	ENST00000971859.1		c.75_77delGCT	p.Leu26del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000641918.1

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

GnomAD2 exomes AF: 0.0917 AC: 11 AN: 120 AF XY: 0.0641

Gnomad AFR exome AF: 0.00

Gnomad ASJ 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

African (AFR) AF: 0.161 AC: 3211 AN: 19958

American (AMR) AF: 0.316 AC: 1605 AN: 5076

Ashkenazi Jewish (ASJ) AF: 0.0985 AC: 1085 AN: 11012

East Asian (EAS) AF: 0.501 AC: 9192 AN: 18344

South Asian (SAS) AF: 0.214 AC: 3997 AN: 18676

European-Finnish (FIN) AF: 0.187 AC: 2689 AN: 14398

Middle Eastern (MID) AF: 0.130 AC: 325 AN: 2496

European-Non Finnish (NFE) AF: 0.204 AC: 176032 AN: 864086

Other (OTH) AF: 0.216 AC: 8054 AN: 37316

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

African (AFR) AF: 0.170 AC: 6922 AN: 40794

American (AMR) AF: 0.309 AC: 4637 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 364 AN: 3450

East Asian (EAS) AF: 0.489 AC: 2335 AN: 4774

South Asian (SAS) AF: 0.219 AC: 1048 AN: 4786

European-Finnish (FIN) AF: 0.214 AC: 2009 AN: 9408

Middle Eastern (MID) AF: 0.156 AC: 45 AN: 288

European-Non Finnish (NFE) AF: 0.200 AC: 13287 AN: 66548

Other (OTH) AF: 0.227 AC: 467 AN: 2054

Alfa AF: 0.119 Hom.: 192

Bravo AF: 0.223

Asia WGS AF: 0.353 AC: 1165 AN: 3316

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=73/27	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34503316; hg19: chr19-18717389; COSMIC: COSV66504134; COSMIC: COSV66504134;