chr15-73126400-A-AT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

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
• 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 4 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: Variant has high frequency in the SAS (0.04) population. However there is too low homozygotes in high coverage region: (expected more than 291, got 0).

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

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

GnomAD2 exomes AF: 0.0322 AC: 3474 AN: 107830 AF XY: 0.0318

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.0359

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0342

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

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

African (AFR) AF: 0.0346 AC: 857 AN: 24744

American (AMR) AF: 0.0269 AC: 814 AN: 30242

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 631 AN: 20548

East Asian (EAS) AF: 0.0229 AC: 764 AN: 33328

South Asian (SAS) AF: 0.0413 AC: 2659 AN: 64380

European-Finnish (FIN) AF: 0.0243 AC: 949 AN: 39086

Middle Eastern (MID) AF: 0.0254 AC: 116 AN: 4560

European-Non Finnish (NFE) AF: 0.0351 AC: 29829 AN: 850860

Other (OTH) AF: 0.0334 AC: 1568 AN: 46884

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

African (AFR) AF: 0.00190 AC: 75 AN: 39490

American (AMR) AF: 0.000694 AC: 10 AN: 14410

Ashkenazi Jewish (ASJ) AF: 0.000299 AC: 1 AN: 3350

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4974

South Asian (SAS) AF: 0.00111 AC: 5 AN: 4514

European-Finnish (FIN) AF: 0.00264 AC: 24 AN: 9096

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

European-Non Finnish (NFE) AF: 0.000306 AC: 20 AN: 65428

Other (OTH) AF: 0.000510 AC: 1 AN: 1960

Alfa AF: 0.0126 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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747845315; hg19: chr15-73418741;