15-73122579-A-G

Variant names:

• chr15-73122579-A-G
• rs142340038
• NM_002499.4:c.503A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002499.4(NEO1):​c.503A>G​(p.Asn168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: NEO1 NM_002499.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.07

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018581271).
• BP6: Variant 15-73122579-A-G is Benign according to our data. Variant chr15-73122579-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2310632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEO1	NM_002499.4	c.503A>G	p.Asn168Ser	missense_variant	Exon 3 of 29	ENST00000261908.11	NP_002490.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEO1	ENST00000261908.11	c.503A>G	p.Asn168Ser	missense_variant	Exon 3 of 29	1	NM_002499.4	ENSP00000261908.6
NEO1	ENST00000558964.5	c.503A>G	p.Asn168Ser	missense_variant	Exon 3 of 28	1		ENSP00000453200.1
NEO1	ENST00000560262.5	c.503A>G	p.Asn168Ser	missense_variant	Exon 3 of 28	1		ENSP00000453317.1
NEO1	ENST00000339362.9	c.503A>G	p.Asn168Ser	missense_variant	Exon 4 of 30	5		ENSP00000341198.5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251400 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135864

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000257 AC: 376 AN: 1461862 Hom.: 3 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 03, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.37
DEOGEN2	Benign	0.043	T;T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	.;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.028
MVP		0.15
MPC		0.14
ClinPred		0.0051	T
GERP RS		0.89
Varity_R		0.041
gMVP		0.075

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: rs142340038; hg19: chr15-73414920;