12-5494741-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001102654.2(NTF3):​c.566T>G​(p.Leu189Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

NTF3
NM_001102654.2 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found
Variant links:
Genes affected
NTF3 (HGNC:8023): (neurotrophin 3) The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system, and may affect development of neurons in the embryo when it is expressed in human placenta. NTF3-deficient mice generated by gene targeting display severe movement defects of the limbs. The mature peptide of this protein is identical in all mammals examined including human, pig, rat and mouse. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTF3NM_001102654.2 linkc.566T>G p.Leu189Arg missense_variant Exon 2 of 2 ENST00000423158.4 NP_001096124.1 P20783-2
NTF3NM_002527.5 linkc.527T>G p.Leu176Arg missense_variant Exon 1 of 1 NP_002518.1 P20783-1
NTF3XM_011520963.3 linkc.527T>G p.Leu176Arg missense_variant Exon 2 of 2 XP_011519265.1 P20783-1
NTF3XM_047428901.1 linkc.527T>G p.Leu176Arg missense_variant Exon 2 of 2 XP_047284857.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NTF3ENST00000423158.4 linkc.566T>G p.Leu189Arg missense_variant Exon 2 of 2 1 NM_001102654.2 ENSP00000397297.2 P20783-2
NTF3ENST00000331010.7 linkc.527T>G p.Leu176Arg missense_variant Exon 1 of 1 6 ENSP00000328738.6 P20783-1
NTF3ENST00000535299.5 linkn.232-11824T>G intron_variant Intron 1 of 4 5
NTF3ENST00000543548.1 linkn.*240T>G downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 01, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.527T>G (p.L176R) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a T to G substitution at nucleotide position 527, causing the leucine (L) at amino acid position 176 to be replaced by an arginine (R). 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
0.93
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
.;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Uncertain
2.6
.;M
PhyloP100
8.0
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
.;D
Vest4
0.97
MutPred
0.88
.;Gain of MoRF binding (P = 0.0045);
MVP
0.97
MPC
2.3
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.95
gMVP
0.96
Mutation Taster
=7/93
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr12-5603907; API