19-49061382-G-A

Variant names:

• chr19-49061382-G-A
• rs121918427
• NM_006179.5:c.616C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter P:1 U:1 B:1
• Conservation: PhyloP100: 1.23
• Publications: 15 publications found

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

ENSG00000283663 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006179.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTF4	NM_006179.5	MANE Select	c.616C>T	p.Arg206Trp	missense	Exon 2 of 2	NP_006170.1
	NTF4	NM_001395489.1		c.616C>T	p.Arg206Trp	missense	Exon 3 of 3	NP_001382418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTF4	ENST00000593537.2	TSL:6 MANE Select	c.616C>T	p.Arg206Trp	missense	Exon 2 of 2	ENSP00000469455.1
	ENSG00000283663	ENST00000599795.5	TSL:2	n.243+373C>T		intron	N/A	ENSP00000470689.1
	NTF4	ENST00000594938.2	TSL:5	c.616C>T	p.Arg206Trp	missense	Exon 3 of 3	ENSP00000512387.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152146 Hom.: 1 Cov.: 32

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

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.: 10 Cov.: 32 AF XY: 0.00119 AC XY: 863 AN XY: 726424

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86176

European-Finnish (FIN) AF: 0.0114 AC: 607 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4524

European-Non Finnish (NFE) AF: 0.000934 AC: 1039 AN: 1111998

Other (OTH) AF: 0.00110 AC: 66 AN: 60256

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74456

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68006

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00146 Hom.: 3

Bravo AF: 0.000691

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00120

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glaucoma 1, open angle, O Pathogenic:1 Uncertain:1

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.

Mar 12, 2010

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

not provided Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NTF4: BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Uncertain	0.73	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.76
ClinPred		0.031	T
GERP RS		0.94
Varity_R		0.44
gMVP		0.75
Mutation Taster		=88/12	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918427; hg19: chr19-49564639; COSMIC: COSV56824774; COSMIC: COSV56824774;