Genetic Variant NM_004750.5:c.1255+32G>T (chr19-18594033-C-A) – ACMG Classification: Likely_benign (-4 pts)

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>T 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 0.000011 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRLF1
NM_004750.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.943

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5 link	c.1255+32G>T		intron_variant	Intron 8 of 8	ENST00000392386.8	NP_004741.1	O75462

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRLF1	ENST00000392386.8 link	c.1255+32G>T	intron_variant	Intron 8 of 8	1	NM_004750.5	ENSP00000376188.2	O75462
CRLF1	ENST00000684169.1 link	c.1260+32G>T	intron_variant	Intron 8 of 8			ENSP00000506849.1	A0A804HI12
CRLF1	ENST00000594325.1 link	n.189+214G>T	intron_variant	Intron 1 of 2	3
CRLF1	ENST00000596360.1 link	n.70+32G>T	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0000108

AC:

AN:

92922

Hom.:

Cov.:

show subpopulations

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:

0.0000216

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000340

AC:

AN:

88194

AF XY:

0.0000409

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

AN:

317426

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

169782

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

7864

American (AMR)

AF:

0.00

AC:

AN:

17916

Ashkenazi Jewish (ASJ)

AF:

0.000296

AC:

AN:

10120

East Asian (EAS)

AF:

0.00

AC:

AN:

11922

South Asian (SAS)

AF:

0.000410

AC:

AN:

48796

European-Finnish (FIN)

AF:

0.0000746

AC:

AN:

26812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1334

European-Non Finnish (NFE)

AF:

0.0000785

AC:

AN:

178304

Other (OTH)

AF:

0.0000696

AC:

AN:

14358

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000108

AC:

AN:

92922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

43716

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24508

American (AMR)

AF:

0.00

AC:

AN:

7970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2420

East Asian (EAS)

AF:

0.00

AC:

AN:

2880

South Asian (SAS)

AF:

0.00

AC:

AN:

2480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

46294

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.6

(source)

DANN

Benign

0.94

PhyloP100

-0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over