chr16-47083554-C-A

Position:

• chr16-47083554-C-A

Variant summary

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

The NM_018092.5(NETO2):​c.1245G>T​(p.Leu415Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NETO2 NM_018092.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550

Genes affected

NETO2 (HGNC:14644): (neuropilin and tolloid like 2) This gene encodes a predicted transmembrane protein containing two extracellular CUB domains followed by a low-density lipoprotein class A (LDLa) domain. A similar gene in rats encodes a protein that modulates glutamate signaling in the brain by regulating kainate receptor function. Expression of this gene may be a biomarker for proliferating infantile hemangiomas. A pseudogene of this gene is located on the long arm of chromosome 8. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

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=0.2823804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NETO2	NM_018092.5	c.1245G>T	p.Leu415Phe	missense_variant	9/9	ENST00000562435.6	NP_060562.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NETO2	ENST00000562435.6	c.1245G>T	p.Leu415Phe	missense_variant	9/9	1	NM_018092.5	ENSP00000455169.1
NETO2	ENST00000303155.9	c.1224G>T	p.Leu408Phe	missense_variant	9/9	5		ENSP00000306726.5
NETO2	ENST00000562559.5	c.762G>T	p.Leu254Phe	missense_variant	5/5	3		ENSP00000454213.1
NETO2	ENST00000564667.1	c.351G>T	p.Leu117Phe	missense_variant	2/2	4		ENSP00000457133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Aug 12, 2024

The c.1245G>T (p.L415F) alteration is located in exon 9 (coding exon 9) of the NETO2 gene. This alteration results from a G to T substitution at nucleotide position 1245, causing the leucine (L) at amino acid position 415 to be replaced by a phenylalanine (F). 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	0.28
BayesDel_addAF	Benign	-0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.028
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.31		Loss of disorder (P = 0.1769);.;
MVP		0.64
MPC		1.0
ClinPred		0.92	D
GERP RS		2.3
Varity_R		0.14
gMVP		0.60

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: chr16-47117465;