12-5494540-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001102654.2(NTF3):c.365G>A(p.Ser122Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NTF3 NM_001102654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043494105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTF3	NM_001102654.2	c.365G>A	p.Ser122Asn	missense_variant	2/2	ENST00000423158.4
NTF3	NM_002527.5	c.326G>A	p.Ser109Asn	missense_variant	1/1
NTF3	XM_011520963.3	c.326G>A	p.Ser109Asn	missense_variant	2/2
NTF3	XM_047428901.1	c.326G>A	p.Ser109Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTF3	ENST00000423158.4	c.365G>A	p.Ser122Asn	missense_variant	2/2	1	NM_001102654.2	P4
NTF3	ENST00000331010.7	c.326G>A	p.Ser109Asn	missense_variant	1/1			A1
NTF3	ENST00000535299.5	n.232-12025G>A		intron_variant, non_coding_transcript_variant		5
NTF3	ENST00000543548.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Aug 14, 2023

The c.326G>A (p.S109N) alteration is located in exon 1 (coding exon 1) of the NTF3 gene. This alteration results from a G to A substitution at nucleotide position 326, causing the serine (S) at amino acid position 109 to be replaced by an asparagine (N). 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	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	22
Dann	Benign	0.26
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.82	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.089
Sift	Benign	1.0	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0	.;B
Vest4		0.075
MutPred		0.33		.;Gain of catalytic residue at S109 (P = 0.0026);
MVP		0.14
MPC		0.81
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.093
gMVP		0.051

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: rs1417380268; hg19: chr12-5603706;