19-18594033-C-G

Variant names:

• chr19-18594033-C-G
• rs1568439434
• NM_004750.5:c.1255+32G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004750.5(CRLF1):​c.1255+32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRLF1 NM_004750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.943
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.1255+32G>C		intron_variant	Intron 8 of 8	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.1255+32G>C		intron_variant	Intron 8 of 8	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.1260+32G>C		intron_variant	Intron 8 of 8			ENSP00000506849.1
CRLF1	ENST00000594325.1	n.189+214G>C		intron_variant	Intron 1 of 2	3
CRLF1	ENST00000596360.1	n.70+32G>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0000215 AC: 2 AN: 92916 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000432

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000794 AC: 7 AN: 88194 AF XY: 0.000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000665

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00169 AC: 536 AN: 316964 Hom.: 0 Cov.: 3 AF XY: 0.00189 AC XY: 320 AN XY: 169504

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000254 AC: 2 AN: 7860

American (AMR) AF: 0.000167 AC: 3 AN: 17916

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 3 AN: 10110

East Asian (EAS) AF: 0.000419 AC: 5 AN: 11922

South Asian (SAS) AF: 0.00380 AC: 185 AN: 48642

European-Finnish (FIN) AF: 0.000933 AC: 25 AN: 26786

Middle Eastern (MID) AF: 0.000750 AC: 1 AN: 1334

European-Non Finnish (NFE) AF: 0.00163 AC: 291 AN: 178052

Other (OTH) AF: 0.00146 AC: 21 AN: 14342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000215 AC: 2 AN: 92916 Hom.: 0 Cov.: 27 AF XY: 0.0000457 AC XY: 2 AN XY: 43716

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24506

American (AMR) AF: 0.00 AC: 0 AN: 7970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2420

East Asian (EAS) AF: 0.00 AC: 0 AN: 2880

South Asian (SAS) AF: 0.00 AC: 0 AN: 2480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.0000432 AC: 2 AN: 46290

Other (OTH) AF: 0.00 AC: 0 AN: 1230

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.8
DANN	Benign	0.82
PhyloP100		-0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1568439434; hg19: chr19-18704843;