NM_013246.3:c.328T>C

Variant names:

• chr11-67365486-A-G
• rs1590912449
• NM_013246.3:c.328T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013246.3(CLCF1):​c.328T>C​(p.Tyr110His) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,756 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

Genes affected

CLCF1 (HGNC:17412): (cardiotrophin like cytokine factor 1) This gene is a member of the glycoprotein (gp)130 cytokine family and encodes cardiotrophin-like cytokine factor 1 (CLCF1). CLCF1 forms a heterodimer complex with cytokine receptor-like factor 1 (CRLF1). This dimer competes with ciliary neurotrophic factor (CNTF) for binding to the ciliary neurotrophic factor receptor (CNTFR) complex, and activates the Jak-STAT signaling cascade. CLCF1 can be actively secreted from cells by forming a complex with soluble type I CRLF1 or soluble CNTFR. CLCF1 is a potent neurotrophic factor, B-cell stimulatory agent and neuroendocrine modulator of pituitary corticotroph function. Defects in CLCF1 cause cold-induced sweating syndrome 2 (CISS2). This syndrome is characterized by a profuse sweating after exposure to cold as well as congenital physical abnormalities of the head and spine. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

ENSG00000256514 (HGNC:):

RAD9A (HGNC:9827): (RAD9 checkpoint clamp component A) This gene product is highly similar to Schizosaccharomyces pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair. This protein possesses 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with RAD1 and HUS1. This complex is recruited by checkpoint protein RAD17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCF1	NM_013246.3	c.328T>C	p.Tyr110His	missense_variant	Exon 3 of 3	ENST00000312438.8	NP_037378.1
CLCF1	NM_001166212.2	c.298T>C	p.Tyr100His	missense_variant	Exon 3 of 3		NP_001159684.1
LOC100130987	NR_024469.1	n.424-22049A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCF1	ENST00000312438.8	c.328T>C	p.Tyr110His	missense_variant	Exon 3 of 3	1	NM_013246.3	ENSP00000309338.7
ENSG00000256514	ENST00000543494.1	c.16+8038T>C		intron_variant	Intron 1 of 3	3		ENSP00000480527.1
CLCF1	ENST00000533438.1	c.298T>C	p.Tyr100His	missense_variant	Exon 3 of 3	2		ENSP00000434122.1
RAD9A	ENST00000622583.4	n.392-22049A>G		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727172

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328T>C (p.Y110H) alteration is located in exon 3 (coding exon 3) of the CLCF1 gene. This alteration results from a T to C substitution at nucleotide position 328, causing the tyrosine (Y) at amino acid position 110 to be replaced by a histidine (H). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.71		Gain of disorder (P = 0.0881);.;
MVP		0.80
MPC		1.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.73
gMVP		0.76

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

Other links and lift over

dbSNP: rs1590912449; hg19: chr11-67132957;