19-18594033-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004750.5(CRLF1):​c.1255+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 27)
  • Exomes 𝑓: 0.012 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRLF1 NM_004750.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.943

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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-18594033-C-T is Benign according to our data. Variant chr19-18594033-C-T is described in ClinVar as [Benign]. Clinvar id is 1231570.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 221 AN: 92050 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00127

Gnomad ASJ AF: 0.00291

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.000405

Gnomad FIN AF: 0.00563

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00328

GnomAD2 exomes AF: 0.0322 AC: 2838 AN: 88194 AF XY: 0.0294

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.0846

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.0626

Gnomad FIN exome AF: 0.00581

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0407

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0116 AC: 3642 AN: 314630 Hom.: 7 Cov.: 3 AF XY: 0.0111 AC XY: 1862 AN XY: 168292

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

African (AFR) AF: 0.0335 AC: 259 AN: 7722

American (AMR) AF: 0.0414 AC: 734 AN: 17748

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 191 AN: 10058

East Asian (EAS) AF: 0.00831 AC: 98 AN: 11792

South Asian (SAS) AF: 0.0107 AC: 520 AN: 48386

European-Finnish (FIN) AF: 0.00583 AC: 155 AN: 26564

Middle Eastern (MID) AF: 0.0129 AC: 17 AN: 1316

European-Non Finnish (NFE) AF: 0.00837 AC: 1480 AN: 176800

Other (OTH) AF: 0.0132 AC: 188 AN: 14244

⚠️ 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: 0.00240 AC: 221 AN: 92102 Hom.: 0 Cov.: 27 AF XY: 0.00277 AC XY: 120 AN XY: 43332

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

African (AFR) AF: 0.00242 AC: 59 AN: 24350

American (AMR) AF: 0.00127 AC: 10 AN: 7902

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 7 AN: 2404

East Asian (EAS) AF: 0.00140 AC: 4 AN: 2858

South Asian (SAS) AF: 0.000404 AC: 1 AN: 2476

European-Finnish (FIN) AF: 0.00563 AC: 24 AN: 4260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00240 AC: 110 AN: 45812

Other (OTH) AF: 0.00325 AC: 4 AN: 1232

⚠️ 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.

Alfa AF: 0.00447 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.1
DANN	Benign	0.95
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

Publications

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Other links and lift over

dbSNP: rs1568439434; hg19: chr19-18704843;