15-73126400-ATTTT-ATTTTTTTT

Variant names:

• chr15-73126400-A-ATTTT
• rs747845315
• NM_002499.4:c.725-6_725-3dupTTTT

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.725-6_725-3dupTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000171 in 1,168,006 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (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 13, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGatc. 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

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000171 AC: 2 AN: 1168006 Hom.: 0 Cov.: 0 AF XY: 0.00000172 AC XY: 1 AN XY: 582544

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

African (AFR) AF: 0.00 AC: 0 AN: 25786

American (AMR) AF: 0.00 AC: 0 AN: 31016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21270

East Asian (EAS) AF: 0.00 AC: 0 AN: 34444

South Asian (SAS) AF: 0.00 AC: 0 AN: 66400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40236

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

European-Non Finnish (NFE) AF: 0.00000223 AC: 2 AN: 895064

Other (OTH) AF: 0.00 AC: 0 AN: 49056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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;