Genetic Variant CRLF1:p.Arg414Gln (chr19-18594079-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004750.5(CRLF1):c.1241G>A(p.Arg414Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000568 in 1,407,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39549586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5 link	c.1241G>A	p.Arg414Gln	missense_variant	Exon 8 of 9	ENST00000392386.8	NP_004741.1	O75462

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRLF1	ENST00000392386.8 link	c.1241G>A	p.Arg414Gln	missense_variant	Exon 8 of 9	1	NM_004750.5	ENSP00000376188.2	O75462
CRLF1	ENST00000684169.1 link	c.1246G>A	p.Gly416Arg	missense_variant	Exon 8 of 9			ENSP00000506849.1	A0A804HI12
CRLF1	ENST00000596360.1 link	n.56G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRLF1	ENST00000594325.1 link	n.189+168G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

168460

AF XY:

0.0000222

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:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000568

AC:

AN:

1407714

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

695110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32292

American (AMR)

AF:

0.00

AC:

AN:

37010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00

AC:

AN:

36794

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00000553

AC:

AN:

1084128

Other (OTH)

AF:

0.0000171

AC:

AN:

58352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000172

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1241G>A (p.R414Q) alteration is located in exon 8 (coding exon 8) of the CRLF1 gene. This alteration results from a G to A substitution at nucleotide position 1241, causing the arginine (R) at amino acid position 414 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.10

PhyloP100

3.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.50

MutPred

0.32

Loss of methylation at R414 (P = 0.0136);

MVP

0.87

MPC

0.48

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.50

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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19-18594079-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over