12-5494440-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001102654.2(NTF3):c.265G>A(p.Gly89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,613,118 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 7 hom. )

Consequence

NTF3
NM_001102654.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.25

Publications

6 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]

NTF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040516257).

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF3	NM_001102654.2 link	c.265G>A	p.Gly89Arg	missense_variant	Exon 2 of 2	ENST00000423158.4	NP_001096124.1	P20783-2
NTF3	NM_002527.5 link	c.226G>A	p.Gly76Arg	missense_variant	Exon 1 of 1		NP_002518.1	P20783-1
NTF3	XM_011520963.3 link	c.226G>A	p.Gly76Arg	missense_variant	Exon 2 of 2		XP_011519265.1	P20783-1
NTF3	XM_047428901.1 link	c.226G>A	p.Gly76Arg	missense_variant	Exon 2 of 2		XP_047284857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NTF3	ENST00000423158.4 link	c.265G>A	p.Gly89Arg	missense_variant	Exon 2 of 2	1	NM_001102654.2	ENSP00000397297.2	P20783-2
NTF3	ENST00000331010.7 link	c.226G>A	p.Gly76Arg	missense_variant	Exon 1 of 1	6		ENSP00000328738.6	P20783-1
NTF3	ENST00000543548.1 link	n.455G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
NTF3	ENST00000535299.5 link	n.232-12125G>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00646

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000905

AC:

225

AN:

248686

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000440

AC:

643

AN:

1460968

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

421

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00559

AC:

482

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52546

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111978

Other (OTH)

AF:

0.000861

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000302

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41540

American (AMR)

AF:

0.000262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00647

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67996

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.000208

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Apr 01, 2015

Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

.;N

PhyloP100

3.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.024

Sift

Benign

0.059

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.0050

.;B

Vest4

0.064

MutPred

0.23

.;Gain of methylation at G76 (P = 0.0231);

MVP

0.12

MPC

1.0

ClinPred

0.025

GERP RS

3.0

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.054

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(source)

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

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12-5494440-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over