12-5494432-A-T

Position:

• chr12-5494432-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102654.2(NTF3):​c.257A>T​(p.Glu86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1408397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.257A>T	p.Glu86Val	missense_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.218A>T	p.Glu73Val	missense_variant	1/1
NTF3	XM_011520963.3	c.218A>T	p.Glu73Val	missense_variant	2/2
NTF3	XM_047428901.1	c.218A>T	p.Glu73Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.257A>T	p.Glu86Val	missense_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.218A>T	p.Glu73Val	missense_variant	1/1			A1
NTF3	ENST00000543548.1	n.447A>T		non_coding_transcript_exon_variant	2/2	3
NTF3	ENST00000535299.5	n.232-12133A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 12, 2024

The c.218A>T (p.E73V) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a A to T substitution at nucleotide position 218, causing the glutamic acid (E) at amino acid position 73 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	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	.;N
MutationTaster	Benign	0.58	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.025
Sift	Benign	0.039	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.0060	.;B
Vest4		0.15
MutPred		0.32		.;Gain of methylation at R74 (P = 0.0417);
MVP		0.30
MPC		1.0
ClinPred		0.14	T
GERP RS		0.81
Varity_R		0.073
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-5603598;