NM_013246.3:c.365G>A

Variant names:

• chr11-67365449-C-T
• rs151050272
• NM_013246.3:c.365G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013246.3(CLCF1):​c.365G>A​(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05160591).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013246.3. 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
	CLCF1	NM_013246.3	MANE Select	c.365G>A	p.Arg122His	missense	Exon 3 of 3	NP_037378.1	Q9UBD9-1
	CLCF1	NM_001166212.2		c.335G>A	p.Arg112His	missense	Exon 3 of 3	NP_001159684.1	Q9UBD9-2
	LOC100130987	NR_024469.1		n.424-22086C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCF1	ENST00000312438.8	TSL:1 MANE Select	c.365G>A	p.Arg122His	missense	Exon 3 of 3	ENSP00000309338.7	Q9UBD9-1
	ENSG00000256514	ENST00000543494.1	TSL:3	c.16+8075G>A		intron	N/A	ENSP00000480527.1	A0A087WWV3
	CLCF1	ENST00000533438.1	TSL:2	c.335G>A	p.Arg112His	missense	Exon 3 of 3	ENSP00000434122.1	Q9UBD9-2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000400 AC: 100 AN: 250138 AF XY: 0.000458

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000771

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000604 AC: 883 AN: 1461496 Hom.: 1 Cov.: 31 AF XY: 0.000594 AC XY: 432 AN XY: 727024

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.000745 AC: 828 AN: 1111870

Other (OTH) AF: 0.000597 AC: 36 AN: 60330

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74350

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0016
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.22
Sift	Uncertain	0.013	D
Sift4G	Benign	0.092	T
Polyphen		0.082	B
Vest4		0.15
MVP		0.61
MPC		0.89
ClinPred		0.032	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.33
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs151050272; hg19: chr11-67132920;