15-73126429-T-C

Variant names:

• chr15-73126429-T-C
• rs780801893
• NM_002499.4:c.737T>C

Variant summary

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

The NM_002499.4(NEO1):​c.737T>C​(p.Ile246Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,440,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I246K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.228
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055993408).

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.737T>C	p.Ile246Thr	missense	Exon 4 of 29	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.737T>C	p.Ile246Thr	missense	Exon 5 of 30	NP_001406460.1
	NEO1	NM_001172624.2		c.737T>C	p.Ile246Thr	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.737T>C	p.Ile246Thr	missense	Exon 4 of 29	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.737T>C	p.Ile246Thr	missense	Exon 4 of 28	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.737T>C	p.Ile246Thr	missense	Exon 4 of 28	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000209 AC: 5 AN: 239354 AF XY: 0.00000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000156

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: 0.00000625 AC: 9 AN: 1440344 Hom.: 0 Cov.: 32 AF XY: 0.00000698 AC XY: 5 AN XY: 716750

African (AFR) AF: 0.00 AC: 0 AN: 32502

American (AMR) AF: 0.000212 AC: 9 AN: 42376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 83104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100196

Other (OTH) AF: 0.00 AC: 0 AN: 59588

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.9
DANN	Benign	0.38
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.015	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.070	N
PhyloP100		0.23
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.11
Sift	Benign	0.59	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.47		Gain of disorder (P = 0.025)
MVP		0.043
MPC		0.23
ClinPred		0.022	T
GERP RS		4.7
Varity_R		0.020
gMVP		0.36

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: rs780801893; hg19: chr15-73418770;