chr18-72858857-C-T

Variant names:

• chr18-72858857-C-T
• NM_138966.5:c.438G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138966.5(NETO1):​c.438G>A​(p.Met146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NETO1 NM_138966.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.475
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18334207).

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.438G>A	p.Met146Ile	missense	Exon 4 of 11	NP_620416.2	Q8TDF5-3
	NETO1	NM_001201465.3		c.438G>A	p.Met146Ile	missense	Exon 4 of 11	NP_001188394.2	Q8TDF5-3
	NETO1	NM_001354017.2		c.438G>A	p.Met146Ile	missense	Exon 4 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.438G>A	p.Met146Ile	missense	Exon 4 of 11	ENSP00000313088.6	Q8TDF5-3
	NETO1	ENST00000583169.5	TSL:1	c.438G>A	p.Met146Ile	missense	Exon 4 of 11	ENSP00000464312.1	Q8TDF5-3
	NETO1	ENST00000397929.5	TSL:1	c.435G>A	p.Met145Ile	missense	Exon 4 of 5	ENSP00000381024.1	Q8TDF5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460672 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726612

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111480

Other (OTH) AF: 0.00 AC: 0 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N
PhyloP100		0.47
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.052
Sift	Benign	0.27	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.43		Gain of catalytic residue at M146 (P = 0.0152)
MVP		0.19
MPC		0.60
ClinPred		0.34	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.14
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr18-70526092; COSMIC: COSV55015181; COSMIC: COSV55015181;