Genetic Variant NTF3:p.Arg149Trp (chr12-5494620-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001102654.2(NTF3):c.445C>T(p.Arg149Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NTF3
NM_001102654.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.119

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]

NTF3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38328952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF3	NM_001102654.2 link	c.445C>T	p.Arg149Trp	missense_variant	Exon 2 of 2	ENST00000423158.4	NP_001096124.1	P20783-2
NTF3	NM_002527.5 link	c.406C>T	p.Arg136Trp	missense_variant	Exon 1 of 1		NP_002518.1	P20783-1
NTF3	XM_011520963.3 link	c.406C>T	p.Arg136Trp	missense_variant	Exon 2 of 2		XP_011519265.1	P20783-1
NTF3	XM_047428901.1 link	c.406C>T	p.Arg136Trp	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.445C>T	p.Arg149Trp	missense_variant	Exon 2 of 2	1	NM_001102654.2	ENSP00000397297.2	P20783-2
NTF3	ENST00000331010.7 link	c.406C>T	p.Arg136Trp	missense_variant	Exon 1 of 1	6		ENSP00000328738.6	P20783-1
NTF3	ENST00000535299.5 link	n.232-11945C>T		intron_variant	Intron 1 of 4	5
NTF3	ENST00000543548.1 link	n.*119C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

.;M

PhyloP100

-0.12

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

.;D

Vest4

0.51

MutPred

0.40

.;Loss of disorder (P = 0.0039);

MVP

0.22

MPC

2.0

ClinPred

0.88

GERP RS

-3.1

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.17

gMVP

0.50

Mutation Taster

=50/50

(source)

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

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chr12-5494620-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over