Genetic Variant NM_004750.5:c.1087G>C (chr19-18594372-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004750.5(CRLF1):c.1087G>C(p.Val363Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V363M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
cold-induced sweating syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
idiopathic achalasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CRLF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10458732).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004750.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF1	NM_004750.5	MANE Select	c.1087G>C	p.Val363Leu	missense	Exon 7 of 9	NP_004741.1	O75462

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRLF1	ENST00000392386.8	TSL:1 MANE Select	c.1087G>C	p.Val363Leu	missense	Exon 7 of 9	ENSP00000376188.2	O75462
CRLF1	ENST00000928241.1		c.1168G>C	p.Val390Leu	missense	Exon 8 of 10	ENSP00000598300.1
CRLF1	ENST00000971859.1		c.1153G>C	p.Val385Leu	missense	Exon 8 of 10	ENSP00000641918.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456202

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109572

Other (OTH)

AF:

0.00

AC:

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.058

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.30

PhyloP100

1.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.020

REVEL

Benign

0.13

Sift

Benign

0.85

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.14

MutPred

0.40

Loss of sheet (P = 0.0181)

MVP

0.61

MPC

0.36

ClinPred

0.26

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.089

gMVP

0.25

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over