NM_002499.4:c.725-3dupT

Variant names:

• chr15-73126400-A-AT
• rs747845315
• NM_002499.4:c.725-3dupT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Moderate PM2 BS1

The NM_002499.4(NEO1):​c.725-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,259,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: NEO1 NM_002499.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035111718 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: taatttttttttttttttAGatc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0343 (38187/1114632) while in subpopulation SAS AF= 0.0413 (2659/64380). AF 95% confidence interval is 0.04. There are 0 homozygotes in gnomad4_exome. There are 18939 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEO1	NM_002499.4	c.725-3dupT		splice_acceptor_variant, intron_variant	Intron 3 of 28	ENST00000261908.11	NP_002490.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEO1	ENST00000261908.11	c.725-17_725-16insT		intron_variant	Intron 3 of 28	1	NM_002499.4	ENSP00000261908.6

Frequencies

GnomAD3 genomes AF: 0.000949 AC: 137 AN: 144360 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000695

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000306

Gnomad OTH AF: 0.000513

GnomAD4 exome AF: 0.0343 AC: 38187 AN: 1114632 Hom.: 0 Cov.: 0 AF XY: 0.0340 AC XY: 18939 AN XY: 556618

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0307

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.0413

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.0351

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.000949 AC: 137 AN: 144390 Hom.: 0 Cov.: 32 AF XY: 0.000969 AC XY: 68 AN XY: 70162

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000694

Gnomad4 ASJ AF: 0.000299

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.000306

Gnomad4 OTH AF: 0.000510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs747845315; hg19: chr15-73418741;