15-73126400-ATTTT-ATTTTTT

Variant names:

• chr15-73126400-A-ATT
• rs747845315
• NM_002499.4:c.725-4_725-3dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_002499.4(NEO1):​c.725-4_725-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,309,992 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: NEO1 NM_002499.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• 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 2 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: aattttttttttttttttAGatc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.725-4_725-3dupTT		splice_acceptor intron	N/A	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.725-4_725-3dupTT		splice_acceptor intron	N/A	NP_001406460.1
	NEO1	NM_001172624.2		c.725-4_725-3dupTT		splice_acceptor intron	N/A	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.725-17_725-16insTT		intron	N/A	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.725-17_725-16insTT		intron	N/A	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.725-17_725-16insTT		intron	N/A	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144420 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000507

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000612 AC: 66 AN: 107830 AF XY: 0.000554

Gnomad AFR exome AF: 0.000543

Gnomad AMR exome AF: 0.000662

Gnomad ASJ exome AF: 0.000859

Gnomad EAS exome AF: 0.000643

Gnomad FIN exome AF: 0.000683

Gnomad NFE exome AF: 0.000524

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000254 AC: 296 AN: 1165540 Hom.: 0 Cov.: 0 AF XY: 0.000263 AC XY: 153 AN XY: 581314

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000233 AC: 6 AN: 25764

American (AMR) AF: 0.000420 AC: 13 AN: 30948

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 8 AN: 21234

East Asian (EAS) AF: 0.000233 AC: 8 AN: 34398

South Asian (SAS) AF: 0.000635 AC: 42 AN: 66150

European-Finnish (FIN) AF: 0.000224 AC: 9 AN: 40186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4734

European-Non Finnish (NFE) AF: 0.000224 AC: 200 AN: 893160

Other (OTH) AF: 0.000204 AC: 10 AN: 48966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 144452 Hom.: 0 Cov.: 32 AF XY: 0.0000285 AC XY: 2 AN XY: 70200

African (AFR) AF: 0.0000506 AC: 2 AN: 39498

American (AMR) AF: 0.00 AC: 0 AN: 14410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65466

Other (OTH) AF: 0.00 AC: 0 AN: 1958

Alfa AF: 0.000402 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
BranchPoint Hunter		5.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747845315; hg19: chr15-73418741;