chr15-73126429-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002499.4(NEO1):​c.737T>A​(p.Ile246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,592,240 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05885309).

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>A	p.Ile246Lys	missense	Exon 4 of 29	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.737T>A	p.Ile246Lys	missense	Exon 5 of 30	NP_001406460.1
	NEO1	NM_001172624.2		c.737T>A	p.Ile246Lys	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>A	p.Ile246Lys	missense	Exon 4 of 29	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.737T>A	p.Ile246Lys	missense	Exon 4 of 28	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.737T>A	p.Ile246Lys	missense	Exon 4 of 28	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1440344 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 716748

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

American (AMR) AF: 0.00 AC: 0 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: 0.00000364 AC: 4 AN: 1100196

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

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151896 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74170

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Uncertain	0.38
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.40
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PhyloP100		0.23
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.11
Sift	Benign	0.89	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.043
MPC		0.32
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.027
gMVP		0.58
Mutation Taster		=96/4	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: rs780801893; hg19: chr15-73418770;