rs193920922

Positions:

• chr12-95737907-G-A

Variant summary

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

The NM_021229.4(NTN4):​c.823C>T​(p.His275Tyr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTN4 NM_021229.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0200

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]

NTN4 (HGNC:):

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=0.09637442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTN4	NM_021229.4	c.823C>T	p.His275Tyr	missense_variant	3/10	ENST00000343702.9	NP_067052.2
NTN4	NM_001329700.2	c.823C>T	p.His275Tyr	missense_variant	3/9		NP_001316629.1
NTN4	NM_001329701.2	c.712C>T	p.His238Tyr	missense_variant	3/10		NP_001316630.1
NTN4	NM_001329702.2	c.712C>T	p.His238Tyr	missense_variant	3/10		NP_001316631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.823C>T	p.His275Tyr	missense_variant	3/10	1	NM_021229.4	ENSP00000340998.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T;.;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.40	T;.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.;.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.083
Sift	Benign	0.037	D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		0.11	B;.;.;B
Vest4		0.16
MutPred		0.55		Gain of catalytic residue at Q270 (P = 0);.;.;Gain of catalytic residue at Q270 (P = 0);
MVP		0.18
MPC		0.41
ClinPred		0.065	T
GERP RS		3.6
Varity_R		0.040
gMVP		0.46

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: rs193920922; hg19: chr12-96131685; COSMIC: COSV59222574; COSMIC: COSV59222574;