15-73052778-A-G

Variant names:

• chr15-73052778-A-G
• rs773350771
• NM_002499.4:c.103A>G

Variant summary

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

The NM_002499.4(NEO1):​c.103A>G​(p.Arg35Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,020,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R35W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00800
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12046626).

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.103A>G	p.Arg35Gly	missense	Exon 1 of 29	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.103A>G	p.Arg35Gly	missense	Exon 2 of 30	NP_001406460.1
	NEO1	NM_001172624.2		c.103A>G	p.Arg35Gly	missense	Exon 2 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.103A>G	p.Arg35Gly	missense	Exon 1 of 29	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.103A>G	p.Arg35Gly	missense	Exon 1 of 28	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.103A>G	p.Arg35Gly	missense	Exon 1 of 28	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000294 AC: 3 AN: 1020636 Hom.: 0 Cov.: 20 AF XY: 0.00000202 AC XY: 1 AN XY: 496114

⚠️ 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: 19540

American (AMR) AF: 0.00 AC: 0 AN: 9196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12190

East Asian (EAS) AF: 0.000170 AC: 3 AN: 17620

South Asian (SAS) AF: 0.00 AC: 0 AN: 36526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 870156

Other (OTH) AF: 0.00 AC: 0 AN: 37578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0338994), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.0080
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.068
Sift	Uncertain	0.014	D
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.45		Loss of helix (P = 0.0017)
MVP		0.25
MPC		0.24
ClinPred		0.074	T
GERP RS		-0.014
PromoterAI		0.022	Neutral
Varity_R		0.16
gMVP		0.44
Mutation Taster		=92/8	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: rs773350771; hg19: chr15-73345119;