12-5494476-A-G

Variant summary

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

The NM_001102654.2(NTF3):c.301A>G(p.Met101Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,613,724 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.664

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=0.003404975).
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.301A>G	p.Met101Val	missense_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.262A>G	p.Met88Val	missense_variant	1/1
NTF3	XM_011520963.3	c.262A>G	p.Met88Val	missense_variant	2/2
NTF3	XM_047428901.1	c.262A>G	p.Met88Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.301A>G	p.Met101Val	missense_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.262A>G	p.Met88Val	missense_variant	1/1			A1
NTF3	ENST00000543548.1	n.491A>G		non_coding_transcript_exon_variant	2/2	3
NTF3	ENST00000535299.5	n.232-12089A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00646

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000885 AC: 222 AN: 250792 Hom.: 1 AF XY: 0.00121 AC XY: 164 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00716

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000447 AC: 654 AN: 1461570 Hom.: 5 Cov.: 36 AF XY: 0.000684 AC XY: 497 AN XY: 727086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00730

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00647

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000663 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.262A>G (p.M88V) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a A to G substitution at nucleotide position 262, causing the methionine (M) at amino acid position 88 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.22
Dann	Benign	0.50
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.79	N;N
REVEL	Benign	0.035
Sift	Benign	0.77	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.059
MutPred		0.34		.;Gain of sheet (P = 0.0827);
MVP		0.12
MPC		0.86
ClinPred		0.025	T
GERP RS		3.2
Varity_R		0.065
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs562958461; hg19: chr12-5603642;