18-72864831-C-T

Variant names:

• chr18-72864831-C-T
• rs780552539
• NM_138966.5:c.197G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138966.5(NETO1):​c.197G>A​(p.Arg66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NETO1 NM_138966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053771794).

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.197G>A	p.Arg66Gln	missense	Exon 3 of 11	NP_620416.2	Q8TDF5-3
	NETO1	NM_001201465.3		c.197G>A	p.Arg66Gln	missense	Exon 3 of 11	NP_001188394.2	Q8TDF5-3
	NETO1	NM_001354017.2		c.197G>A	p.Arg66Gln	missense	Exon 3 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.197G>A	p.Arg66Gln	missense	Exon 3 of 11	ENSP00000313088.6	Q8TDF5-3
	NETO1	ENST00000583169.5	TSL:1	c.197G>A	p.Arg66Gln	missense	Exon 3 of 11	ENSP00000464312.1	Q8TDF5-3
	NETO1	ENST00000397929.5	TSL:1	c.194G>A	p.Arg65Gln	missense	Exon 3 of 5	ENSP00000381024.1	Q8TDF5-1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000957 AC: 24 AN: 250662 AF XY: 0.0000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461296 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.000247 AC: 11 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86078

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00268 AC: 41 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.0000412 AC: 5

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	0.097
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.085
Sift	Benign	0.27	T
Sift4G	Benign	0.15	T
Polyphen		0.13	B
Vest4		0.27
MutPred		0.52		Loss of sheet (P = 0.0315)
MVP		0.56
MPC		0.69
ClinPred		0.062	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.61
Mutation Taster		=79/21	polymorphism

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: rs780552539; hg19: chr18-70532066;