chr15-73052734-G-A

Position:

• chr15-73052734-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002499.4(NEO1):​c.59G>A​(p.Cys20Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000034 in 1,175,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13965315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEO1	NM_002499.4	c.59G>A	p.Cys20Tyr	missense_variant	1/29	ENST00000261908.11	NP_002490.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEO1	ENST00000261908.11	c.59G>A	p.Cys20Tyr	missense_variant	1/29	1	NM_002499.4	ENSP00000261908.6
NEO1	ENST00000558964.5	c.59G>A	p.Cys20Tyr	missense_variant	1/28	1		ENSP00000453200.1
NEO1	ENST00000560262.5	c.59G>A	p.Cys20Tyr	missense_variant	1/28	1		ENSP00000453317.1
NEO1	ENST00000339362.9	c.59G>A	p.Cys20Tyr	missense_variant	2/30	5		ENSP00000341198.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000340 AC: 4 AN: 1175078 Hom.: 0 Cov.: 30 AF XY: 0.00000520 AC XY: 3 AN XY: 577032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ExAC AF: 0.0000113 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2024

The c.59G>A (p.C20Y) alteration is located in exon 1 (coding exon 1) of the NEO1 gene. This alteration results from a G to A substitution at nucleotide position 59, causing the cysteine (C) at amino acid position 20 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.75	.;T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.026	D;D;T;D
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.32
MutPred		0.49		Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);
MVP		0.22
MPC		0.51
ClinPred		0.068	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs778522110; hg19: chr15-73345075;