chr9-34552312-T-C

Position:

• chr9-34552312-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147164.3(CNTFR):​c.967A>G​(p.Thr323Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000792 in 1,388,062 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: CNTFR NM_147164.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

CNTFR (HGNC:2170): (ciliary neurotrophic factor receptor) This gene encodes a member of the type 1 cytokine receptor family. The encoded protein is the ligand-specific component of a tripartite receptor for ciliary neurotrophic factor, which plays a critical role in neuronal cell survival, differentiation and gene expression. Binding of ciliary neurotrophic factor to the encoded protein recruits the transmembrane components of the receptor, gp130 and leukemia inhibitory factor receptor, facilitating signal transduction. Single nucleotide polymorphisms in this gene may be associated with variations in muscle strength, as well as early onset of eating disorders. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2011]

ACMG classification

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=0.16759026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTFR	NM_147164.3	c.967A>G	p.Thr323Ala	missense_variant	9/10	ENST00000378980.8	NP_671693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTFR	ENST00000378980.8	c.967A>G	p.Thr323Ala	missense_variant	9/10	1	NM_147164.3	ENSP00000368265.3
CNTFR	ENST00000351266.8	c.967A>G	p.Thr323Ala	missense_variant	8/9	1		ENSP00000242338.4
CNTFR	ENST00000610543.4	c.967A>G	p.Thr323Ala	missense_variant	9/10	5		ENSP00000480451.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000792 AC: 11 AN: 1388062 Hom.: 0 Cov.: 32 AF XY: 0.0000102 AC XY: 7 AN XY: 684964

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000927

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.967A>G (p.T323A) alteration is located in exon 9 (coding exon 7) of the CNTFR gene. This alteration results from a A to G substitution at nucleotide position 967, causing the threonine (T) at amino acid position 323 to be replaced by an alanine (A). 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	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.085
Sift	Benign	0.19	T;T;.
Sift4G	Uncertain	0.057	T;T;T
Polyphen		0.060	B;B;B
Vest4		0.21
MutPred		0.16		Loss of glycosylation at T323 (P = 9e-04);Loss of glycosylation at T323 (P = 9e-04);Loss of glycosylation at T323 (P = 9e-04);
MVP		0.46
MPC		0.86
ClinPred		0.54	D
GERP RS		4.5
Varity_R		0.11
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1356214979; hg19: chr9-34552310;