12-5494565-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001102654.2(NTF3):​c.390G>T​(p.Leu130Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L130S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NTF3
NM_001102654.2 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.400

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15658185).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTF3NM_001102654.2 linkc.390G>T p.Leu130Phe missense_variant Exon 2 of 2 ENST00000423158.4 NP_001096124.1 P20783-2
NTF3NM_002527.5 linkc.351G>T p.Leu117Phe missense_variant Exon 1 of 1 NP_002518.1 P20783-1
NTF3XM_011520963.3 linkc.351G>T p.Leu117Phe missense_variant Exon 2 of 2 XP_011519265.1 P20783-1
NTF3XM_047428901.1 linkc.351G>T p.Leu117Phe 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.390G>T p.Leu130Phe missense_variant Exon 2 of 2 1 NM_001102654.2 ENSP00000397297.2 P20783-2
NTF3ENST00000331010.7 linkc.351G>T p.Leu117Phe missense_variant Exon 1 of 1 6 ENSP00000328738.6 P20783-1
NTF3ENST00000535299.5 linkn.232-12000G>T intron_variant Intron 1 of 4 5
NTF3ENST00000543548.1 linkn.*64G>T downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251370
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461860
Hom.:
0
Cov.:
36
AF XY:
0.00000825
AC XY:
6
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.000239
AC:
8
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.000193
AC:
8
AN:
41424
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
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:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.556
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 12, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.351G>T (p.L117F) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a G to T substitution at nucleotide position 351, causing the leucine (L) at amino acid position 117 to be replaced by a phenylalanine (F). 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
Uncertain
0.34
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
.;D
Eigen
Benign
-0.027
Eigen_PC
Benign
-0.022
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.8
.;M
PhyloP100
0.40
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Benign
0.17
Sift
Benign
0.098
T;D
Sift4G
Uncertain
0.046
D;D
Polyphen
0.58
.;P
Vest4
0.37
MutPred
0.22
.;Loss of disorder (P = 0.1108);
MVP
0.35
MPC
2.0
ClinPred
0.13
T
GERP RS
1.4
PromoterAI
-0.018
Neutral
Varity_R
0.27
gMVP
0.59
Mutation Taster
=62/38
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

Publications

Other links and lift over

dbSNP: rs143340870; hg19: chr12-5603731; API