19-18596711-C-A

Position:

chr19-18596711-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_004750.5(CRLF1):c.935G>T(p.Arg312Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.35

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 made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 104) in uniprot entity CRLF1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_004750.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 19-18596711-C-A is Pathogenic according to our data. Variant chr19-18596711-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929437.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF1	NM_004750.5 linkuse as main transcript	c.935G>T	p.Arg312Leu	missense_variant	6/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRLF1	ENST00000392386.8 linkuse as main transcript	c.935G>T	p.Arg312Leu	missense_variant	6/9	1	NM_004750.5	P1
CRLF1	ENST00000684169.1 linkuse as main transcript	c.935G>T	p.Arg312Leu	missense_variant	6/9
CRLF1	ENST00000597131.1 linkuse as main transcript	c.401G>T	p.Arg134Leu	missense_variant	3/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250878

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cold-induced sweating syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Hacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of Medicine

Jun 01, 2020

Sequencing analysis of the CRLF1 gene identified a novel homozygous missense variant (c.935G>T; p.Arg312Leu) in a patient whose clinical features were compatible with Crisponi syndrome. The R312L variant has not been reported in 1000 Genomes Project database and there is only one heterozygous individual in gnomAD data (allele frequency= 0.00000399). This variant was classified as likely pathogenic according to the ACMG guidelines and predicted to be deleterious by in silico pathogenicity prediction tools such as PolyPhen-2 and MutationTaster. Furthermore, alternative variants resulting in different amino acid substitutions at position 312 in CRLF1 have been associated with Crisponi syndrome (Piras et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MutPred

0.79

Loss of MoRF binding (P = 0.0858);

MVP

0.95

MPC

1.3

ClinPred

1.0

GERP RS

5.0

Varity_R

0.83

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over