12-5494440-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001102654.2(NTF3):c.265G>A(p.Gly89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,613,118 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. G89E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (7 hom.)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.25

Genes affected

NTF3 (HGNC:8023): (neurotrophin 3) The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system, and may affect development of neurons in the embryo when it is expressed in human placenta. NTF3-deficient mice generated by gene targeting display severe movement defects of the limbs. The mature peptide of this protein is identical in all mammals examined including human, pig, rat and mouse. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040516257).
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.265G>A	p.Gly89Arg	missense_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.226G>A	p.Gly76Arg	missense_variant	1/1
NTF3	XM_011520963.3	c.226G>A	p.Gly76Arg	missense_variant	2/2
NTF3	XM_047428901.1	c.226G>A	p.Gly76Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.265G>A	p.Gly89Arg	missense_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.226G>A	p.Gly76Arg	missense_variant	1/1			A1
NTF3	ENST00000543548.1	n.455G>A		non_coding_transcript_exon_variant	2/2	3
NTF3	ENST00000535299.5	n.232-12125G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00646

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000905 AC: 225 AN: 248686 Hom.: 1 AF XY: 0.00108 AC XY: 146 AN XY: 134842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000440 AC: 643 AN: 1460968 Hom.: 7 Cov.: 31 AF XY: 0.000579 AC XY: 421 AN XY: 726846

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00559

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74366

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00647

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000446 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville.

Apr 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.024
Sift	Benign	0.059	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0050	.;B
Vest4		0.064
MutPred		0.23		.;Gain of methylation at G76 (P = 0.0231);
MVP		0.12
MPC		1.0
ClinPred		0.025	T
GERP RS		3.0
Varity_R		0.054
gMVP		0.13

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

Other links and lift over

dbSNP: rs540320780; hg19: chr12-5603606; COSMIC: COSV100451186;