chr12-5494681-G-A

Variant names:

• chr12-5494681-G-A
• NM_001102654.2:c.506G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001102654.2(NTF3):​c.506G>A​(p.Ser169Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 10.0
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF3	NM_001102654.2	c.506G>A	p.Ser169Asn	missense_variant	Exon 2 of 2	ENST00000423158.4	NP_001096124.1
NTF3	NM_002527.5	c.467G>A	p.Ser156Asn	missense_variant	Exon 1 of 1		NP_002518.1
NTF3	XM_011520963.3	c.467G>A	p.Ser156Asn	missense_variant	Exon 2 of 2		XP_011519265.1
NTF3	XM_047428901.1	c.467G>A	p.Ser156Asn	missense_variant	Exon 2 of 2		XP_047284857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTF3	ENST00000423158.4	c.506G>A	p.Ser169Asn	missense_variant	Exon 2 of 2	1	NM_001102654.2	ENSP00000397297.2
NTF3	ENST00000331010.7	c.467G>A	p.Ser156Asn	missense_variant	Exon 1 of 1	6		ENSP00000328738.6
NTF3	ENST00000535299.5	n.232-11884G>A		intron_variant	Intron 1 of 4	5
NTF3	ENST00000543548.1	n.*180G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467G>A (p.S156N) 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 467, causing the serine (S) at amino acid position 156 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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.4	.;L
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.094	T;T
Polyphen		0.97	.;D
Vest4		0.86
MutPred		0.88		.;Loss of phosphorylation at S156 (P = 0.0716);
MVP		0.62
MPC		1.6
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.77
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-5603847;