NM_002499.4:c.747G>T

Variant names:

• chr15-73126439-G-T
• rs745561049
• NM_002499.4:c.747G>T

Variant summary

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

The NM_002499.4(NEO1):​c.747G>T​(p.Leu249Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,428 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.04
• Publications: 0 publications found

Genes affected

NEO1 (HGNC:7754): (neogenin 1) This gene encodes a cell surface protein that is a member of the immunoglobulin superfamily. The encoded protein consists of four N-terminal immunoglobulin-like domains, six fibronectin type III domains, a transmembrane domain and a C-terminal internal domain that shares homology with the tumor suppressor candidate gene DCC. This protein may be involved in cell growth and differentiation and in cell-cell adhesion. Defects in this gene are associated with cell proliferation in certain cancers. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002499.4. 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
	NEO1	NM_002499.4	MANE Select	c.747G>T	p.Leu249Phe	missense	Exon 4 of 29	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.747G>T	p.Leu249Phe	missense	Exon 5 of 30	NP_001406460.1
	NEO1	NM_001172624.2		c.747G>T	p.Leu249Phe	missense	Exon 5 of 29	NP_001166095.1	Q92859-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEO1	ENST00000261908.11	TSL:1 MANE Select	c.747G>T	p.Leu249Phe	missense	Exon 4 of 29	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.747G>T	p.Leu249Phe	missense	Exon 4 of 28	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.747G>T	p.Leu249Phe	missense	Exon 4 of 28	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240404 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449428 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720884

African (AFR) AF: 0.00 AC: 0 AN: 32808

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25668

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107426

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.27
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.54
MutPred		0.56		Loss of loop (P = 0.0986)
MVP		0.068
MPC		0.70
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745561049; hg19: chr15-73418780; COSMIC: COSV99982599;