Variant 19-49061658-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006179.5(NTF4):c.340C>T(p.Arg114Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,474 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. R114G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

NTF4
NM_006179.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0660

Variant links:

Genes affected

NTF4 (HGNC:8024): (neurotrophin 4) This gene is a member of a family of neurotrophic factors, neurotrophins, that control survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and less influenced by environmental signals. While knock-outs of other neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 prove lethal during early postnatal development, NTF5-deficient mice only show minor cellular deficits and develop normally to adulthood. [provided by RefSeq, Jul 2008]

NTF4 links:

ENSG00000283663 (HGNC:):

ENSG00000283663 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27016717).

BS2

High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTF4	NM_006179.5 linkuse as main transcript	c.340C>T	p.Arg114Cys	missense_variant	2/2	ENST00000593537.2	NP_006170.1	P34130A0A024QZE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTF4	ENST00000593537.2 linkuse as main transcript	c.340C>T	p.Arg114Cys	missense_variant	2/2	6	NM_006179.5	ENSP00000469455.1		P34130
ENSG00000283663	ENST00000599795.5 linkuse as main transcript	n.243+97C>T		intron_variant		2		ENSP00000470689.1		M0QZQ0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248504

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461268

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2024

The c.340C>T (p.R114C) alteration is located in exon 2 (coding exon 1) of the NTF4 gene. This alteration results from a C to T substitution at nucleotide position 340, causing the arginine (R) at amino acid position 114 to be replaced by a cysteine (C). 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

0.84

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.065

FATHMM_MKL

Benign

0.14

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.70

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;.

Vest4

0.37

MutPred

0.43

Loss of MoRF binding (P = 0.0224);Loss of MoRF binding (P = 0.0224);

MVP

0.82

ClinPred

0.49

GERP RS

3.5

Varity_R

0.18

gMVP

0.46

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

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