rs121918427

Positions:

chr19-49061382-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5PP5BP4BS2

The NM_006179.5(NTF4):c.616C>T(p.Arg206Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,612,428 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts 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. R206Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 10 hom. )

Consequence

NTF4
NM_006179.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided P:1U:1

Conservation

PhyloP100: 1.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-49061381-C-T is described in Lovd as [Pathogenic].

PP5

Variant 19-49061382-G-A is Pathogenic according to our data. Variant chr19-49061382-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 14018.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}. Variant chr19-49061382-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.014867276). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTF4	NM_006179.5 linkuse as main transcript	c.616C>T	p.Arg206Trp	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.616C>T	p.Arg206Trp	missense_variant	2/2	6	NM_006179.5	ENSP00000469455.1		P34130
ENSG00000283663	ENST00000599795.5 linkuse as main transcript	n.243+373C>T		intron_variant		2		ENSP00000470689.1		M0QZQ0

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00169

AC:

423

AN:

249798

Hom.:

AF XY:

0.00168

AC XY:

228

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.0000630

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00119

AC:

1743

AN:

1460164

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

863

AN XY:

726424

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.000934

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152264

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.00172

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00152

AC:

185

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00120

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, O

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_006179.4:c.616C>T in NTF4 gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database. Expression of recombinant NT-4 carrying the R206W mutation was demonstrated to lead to decreased activation of TrkB (PMID19765683). However, a higher frequency of this variant in controls than cases was observed (PMID: 20215012). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationTaster and REVELTaken together, we interprete this variant as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP3, PS3. -
Pathogenic, flagged submission	literature only	OMIM	Mar 12, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Benign

0.14

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.68

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.73

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.66

MVP

0.76

ClinPred

0.031

GERP RS

0.94

Varity_R

0.44

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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