12-95670124-C-G

Position:

• chr12-95670124-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000343702.9(NTN4):​c.1533G>C​(p.Gln511His) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTN4 ENST00000343702.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0110

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]

PGAM1P5 (HGNC:42452): (phosphoglycerate mutase 1 pseudogene 5)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27085647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTN4	NM_021229.4	c.1533G>C	p.Gln511His	missense_variant	8/10	ENST00000343702.9	NP_067052.2
PGAM1P5	NR_077225.1	n.247-367C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.1533G>C	p.Gln511His	missense_variant	8/10	1	NM_021229.4	ENSP00000340998	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

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

Jun 10, 2024

The c.1533G>C (p.Q511H) alteration is located in exon 8 (coding exon 8) of the NTN4 gene. This alteration results from a G to C substitution at nucleotide position 1533, causing the glutamine (Q) at amino acid position 511 to be replaced by a histidine (H). 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	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.73	D;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.90	P;.;.
Vest4		0.45
MutPred		0.45		Gain of catalytic residue at K509 (P = 0.0029);.;.;
MVP		0.35
MPC		0.86
ClinPred		0.42	T
GERP RS		0.58
Varity_R		0.090
gMVP		0.72

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: chr12-96063900;