NM_002499.4:c.725-4_725-3delTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_002499.4(NEO1):​c.725-4_725-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,277,346 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (0 hom.)
• Consequence: NEO1 NM_002499.4 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.346
• 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 1 ACMG points.

• PM2: Variant has high frequency in the AMR (0.006) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).
• BP6: Variant 15-73126400-ATT-A is Benign according to our data. Variant chr15-73126400-ATT-A is described in ClinVar as Benign. ClinVar VariationId is 3044362.Status of the report is no_assertion_criteria_provided, 0 stars.

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_725-3delTT		splice_region intron	N/A	NP_002490.2	Q92859-1
	NEO1	NM_001419531.1		c.725-4_725-3delTT		splice_region intron	N/A	NP_001406460.1
	NEO1	NM_001172624.2		c.725-4_725-3delTT		splice_region 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.725-16_725-15delTT		intron	N/A	ENSP00000261908.6	Q92859-1
	NEO1	ENST00000558964.5	TSL:1	c.725-16_725-15delTT		intron	N/A	ENSP00000453200.1	Q92859-4
	NEO1	ENST00000560262.5	TSL:1	c.725-16_725-15delTT		intron	N/A	ENSP00000453317.1	Q92859-3

Frequencies

GnomAD3 genomes AF: 0.0000208 AC: 3 AN: 144366 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000306

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00782 AC: 843 AN: 107830 AF XY: 0.00754

Gnomad AFR exome AF: 0.00651

Gnomad AMR exome AF: 0.00985

Gnomad ASJ exome AF: 0.00966

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00820

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00331 AC: 3754 AN: 1132980 Hom.: 0 AF XY: 0.00346 AC XY: 1958 AN XY: 565124

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

African (AFR) AF: 0.00312 AC: 78 AN: 25040

American (AMR) AF: 0.00675 AC: 204 AN: 30234

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 92 AN: 20662

East Asian (EAS) AF: 0.00331 AC: 111 AN: 33518

South Asian (SAS) AF: 0.00651 AC: 418 AN: 64176

European-Finnish (FIN) AF: 0.00295 AC: 116 AN: 39270

Middle Eastern (MID) AF: 0.00239 AC: 11 AN: 4604

European-Non Finnish (NFE) AF: 0.00293 AC: 2542 AN: 867808

Other (OTH) AF: 0.00382 AC: 182 AN: 47668

⚠️ 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: 0.0000208 AC: 3 AN: 144366 Hom.: 0 Cov.: 32 AF XY: 0.0000428 AC XY: 3 AN XY: 70116

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

African (AFR) AF: 0.00 AC: 0 AN: 39422

American (AMR) AF: 0.00 AC: 0 AN: 14396

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.00 AC: 0 AN: 4532

European-Finnish (FIN) AF: 0.000110 AC: 1 AN: 9076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000306 AC: 2 AN: 65458

Other (OTH) AF: 0.00 AC: 0 AN: 1948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00657 Hom.: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NEO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747845315; hg19: chr15-73418741;