rs139149169

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000614.4(CNTF):c.83G>A(p.Arg28His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

CNTF
NM_000614.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

CNTF (HGNC:2169): (ciliary neurotrophic factor) The protein encoded by this gene is a polypeptide hormone whose actions appear to be restricted to the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. A read-through transcript variant composed of the upstream ZFP91 gene and CNTF sequence has been identified, but it is thought to be non-coding. Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Oct 2010]

CNTF links:

ZFP91-CNTF (HGNC:33441): (ZFP91-CNTF readthrough (NMD candidate)) This gene represents a read-through transcript composed of ZFP91 and CNTF sequence. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Aug 2008]

ZFP91-CNTF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.070849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTF	NM_000614.4 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2	ENST00000361987.6	NP_000605.1	P26441
ZFP91-CNTF	NR_024091.1 link	n.1813G>A		non_coding_transcript_exon_variant	Exon 12 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTF	ENST00000361987.6 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2	1	NM_000614.4	ENSP00000355370.4	P26441
ZFP91-CNTF	ENST00000389919.8 link	n.*55G>A		non_coding_transcript_exon_variant	Exon 12 of 13	2		ENSP00000455911.1	A0A0A6YYC7
ZFP91-CNTF	ENST00000389919.8 link	n.*55G>A		3_prime_UTR_variant	Exon 12 of 13	2		ENSP00000455911.1	A0A0A6YYC7

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000474

AC:

119

AN:

250828

Hom.:

AF XY:

0.000435

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000891

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000819

AC:

1197

AN:

1461634

Hom.:

Cov.:

AF XY:

0.000799

AC XY:

581

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152262

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000777

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83G>A (p.R28H) alteration is located in exon 1 (coding exon 1) of the CNTF gene. This alteration results from a G to A substitution at nucleotide position 83, causing the arginine (R) at amino acid position 28 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

Benign

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.70

M_CAP

Benign

0.013

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.092

Sift

Uncertain

0.028

Sift4G

Pathogenic

0.0

Polyphen

0.045

Vest4

0.41

MVP

0.67

MPC

0.026

ClinPred

0.070

GERP RS

2.3

Varity_R

0.31

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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