12-95710569-G-A

Position:

• chr12-95710569-G-A

Variant summary

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

The ENST00000343702.9(NTN4):​c.1052C>T​(p.Ser351Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTN4 ENST00000343702.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

Genes affected

NTN4 (HGNC:13658): (netrin 4) This gene encodes a member of the netrin family of proteins, which function in various biological processes including axon guidance, tumorogenesis, and angiogenesis. Netrins are laminin-related proteins that have an N-terminal laminin-type domain, epidermal growth factor-like repeat domain, and a positively charged heparin-binding domain at the C-terminus. The protein encoded by this gene is involved in processes including neurite growth and migration, angiogenesis and mural cell adhesion to endothelial cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTN4	NM_021229.4	c.1052C>T	p.Ser351Leu	missense_variant	5/10	ENST00000343702.9	NP_067052.2
NTN4	NM_001329700.2	c.1052C>T	p.Ser351Leu	missense_variant	5/9		NP_001316629.1
NTN4	NM_001329701.2	c.941C>T	p.Ser314Leu	missense_variant	5/10		NP_001316630.1
NTN4	NM_001329702.2	c.941C>T	p.Ser314Leu	missense_variant	5/10		NP_001316631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.1052C>T	p.Ser351Leu	missense_variant	5/10	1	NM_021229.4	ENSP00000340998	P1

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

Dec 08, 2023

The c.1052C>T (p.S351L) alteration is located in exon 5 (coding exon 5) of the NTN4 gene. This alteration results from a C to T substitution at nucleotide position 1052, causing the serine (S) at amino acid position 351 to be replaced by a leucine (L). 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	0.27
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;.;.;P
Vest4		0.69
MutPred		0.53		Gain of catalytic residue at S355 (P = 5e-04);.;.;Gain of catalytic residue at S355 (P = 5e-04);
MVP		0.51
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.83

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: chr12-96104347;