Variant chr19-18594073-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004750.5(CRLF1):c.1247C>G(p.Thr416Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,061,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.31

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21330181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF1	NM_004750.5 linkuse as main transcript	c.1247C>G	p.Thr416Arg	missense_variant	8/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRLF1	ENST00000392386.8 linkuse as main transcript	c.1247C>G	p.Thr416Arg	missense_variant	8/9	1	NM_004750.5	P1
CRLF1	ENST00000684169.1 linkuse as main transcript	c.1252C>G	p.Arg418Gly	missense_variant	8/9
CRLF1	ENST00000596360.1 linkuse as main transcript	n.62C>G		non_coding_transcript_exon_variant	1/2	2
CRLF1	ENST00000594325.1 linkuse as main transcript	n.189+174C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000377

AC:

AN:

1061962

Hom.:

Cov.:

AF XY:

0.00000574

AC XY:

AN XY:

522428

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000477

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The c.1247C>G (p.T416R) alteration is located in exon 8 (coding exon 8) of the CRLF1 gene. This alteration results from a C to G substitution at nucleotide position 1247, causing the threonine (T) at amino acid position 416 to be replaced by an arginine (R). 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

0.10

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.14

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.49

M_CAP

Benign

0.072

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.60

MutationTaster

Benign

0.85

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.62

REVEL

Benign

0.22

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0060

Polyphen

0.026

Vest4

0.33

MutPred

0.23

Gain of methylation at T416 (P = 0.0037);

MVP

0.86

MPC

0.44

ClinPred

0.94

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over