rs121918427

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206Q) has been classified as Uncertain significance.

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

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

glaucoma 1, open angle, O
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NTF4 links:

ENSG00000283663 (HGNC:):

ENSG00000283663 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014867276).

BP6

Variant 19-49061382-G-A is Benign according to our data. Variant chr19-49061382-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 14018.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF4	NM_006179.5 link	c.616C>T	p.Arg206Trp	missense_variant	Exon 2 of 2	ENST00000593537.2	NP_006170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTF4	ENST00000593537.2 link	c.616C>T	p.Arg206Trp	missense_variant	Exon 2 of 2	6	NM_006179.5	ENSP00000469455.1
ENSG00000283663	ENST00000599795.5 link	n.243+373C>T		intron_variant	Intron 3 of 6	2		ENSP00000470689.1

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

GnomAD2 exomes

AF:

0.00169

AC:

423

AN:

249798

AF XY:

0.00168

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33438

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.0114

AC:

607

AN:

53212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

0.000934

AC:

1039

AN:

1111998

Other (OTH)

AF:

0.00110

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00168

AC:

256

AN:

152264

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0121

AC:

129

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

68006

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00146

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

Mar 12, 2010

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

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. -

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

(source)

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

PhyloP100

1.2

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

Mutation Taster

=88/12

disease causing (ClinVar)

(source)

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

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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