chr18-72783863-T-G

Position:

• chr18-72783863-T-G

Variant summary

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

The NM_138966.5(NETO1):​c.683A>C​(p.Glu228Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NETO1 NM_138966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

Genes affected

NETO1 (HGNC:13823): (neuropilin and tolloid like 1) This gene encodes a transmembrane protein containing two extracellular CUB domains followed by a low-density lipoprotein class A (LDLa) domain. This protein is thought to play a critical role in spatial learning and memory by regulating the function of synaptic N-methyl-D-aspartic acid receptor complexes in the hippocampus. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2017]

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
NETO1	NM_138966.5	c.683A>C	p.Glu228Ala	missense_variant	7/11	ENST00000327305.11	NP_620416.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NETO1	ENST00000327305.11	c.683A>C	p.Glu228Ala	missense_variant	7/11	1	NM_138966.5	ENSP00000313088.6
NETO1	ENST00000583169.5	c.683A>C	p.Glu228Ala	missense_variant	7/11	1		ENSP00000464312.1
NETO1	ENST00000579730.2	n.346A>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Feb 06, 2023

The c.683A>C (p.E228A) alteration is located in exon 7 (coding exon 7) of the NETO1 gene. This alteration results from a A to C substitution at nucleotide position 683, causing the glutamic acid (E) at amino acid position 228 to be replaced by an alanine (A). 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	0.73
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.97	D;D
Vest4		0.69
MutPred		0.64		Loss of disorder (P = 0.0745);Loss of disorder (P = 0.0745);
MVP		0.44
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.82

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: chr18-70451098;