NM_138966.5:c.1324G>A

Variant names:

• chr18-72750279-C-T
• rs780303817
• NM_138966.5:c.1324G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138966.5(NETO1):​c.1324G>A​(p.Gly442Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NETO1 NM_138966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34515393).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138966.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NETO1	NM_138966.5	MANE Select	c.1324G>A	p.Gly442Ser	missense	Exon 9 of 11	NP_620416.2	Q8TDF5-3
	NETO1	NM_001201465.3		c.1324G>A	p.Gly442Ser	missense	Exon 9 of 11	NP_001188394.2	Q8TDF5-3
	NETO1	NM_001354017.2		c.1324G>A	p.Gly442Ser	missense	Exon 9 of 11	NP_001340946.2	Q8TDF5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NETO1	ENST00000327305.11	TSL:1 MANE Select	c.1324G>A	p.Gly442Ser	missense	Exon 9 of 11	ENSP00000313088.6	Q8TDF5-3
	NETO1	ENST00000583169.5	TSL:1	c.1324G>A	p.Gly442Ser	missense	Exon 9 of 11	ENSP00000464312.1	Q8TDF5-3
	NETO1	ENST00000916241.1		c.1408G>A	p.Gly470Ser	missense	Exon 10 of 12	ENSP00000586300.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251012 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461802 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.90	P
Vest4		0.47
MutPred		0.19		Loss of sheet (P = 3e-04)
MVP		0.75
MPC		1.3
ClinPred		0.48	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.28
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs780303817; hg19: chr18-70417514; COSMIC: COSV55015379; COSMIC: COSV55015379;