rs121918427

chr19-49061382-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong 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 Conflicting classifications of pathogenicity (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
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-49061381-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14019.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014867276).
• BS2: High AC in GnomAd at 256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF4	NM_006179.5	c.616C>T	p.Arg206Trp	missense_variant	2/2	ENST00000593537.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF4	ENST00000593537.2	c.616C>T	p.Arg206Trp	missense_variant	2/2		NM_006179.5	P1

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

GnomAD3 exomes AF: 0.00169 AC: 423 AN: 249798 Hom.: 1 AF XY: 0.00168 AC XY: 228 AN XY: 135508

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

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.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74456

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.: 2

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 12, 2010	- -
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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A
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

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

Other links and lift over

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