chr15-73135883-T-A

Position:

• chr15-73135883-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002499.4(NEO1):​c.879-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,426,022 control chromosomes in the GnomAD database, including 5,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1935 hom., cov: 29)
  • Exomes 𝑓: 0.076 (3486 hom.)
• Consequence: NEO1 NM_002499.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01718
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.88

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-73135883-T-A is Benign according to our data. Variant chr15-73135883-T-A is described in ClinVar as [Benign]. Clinvar id is 771006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEO1	NM_002499.4	c.879-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261908.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEO1	ENST00000261908.11	c.879-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002499.4	A2
NEO1	ENST00000558964.5	c.879-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P4
NEO1	ENST00000560262.5	c.879-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
NEO1	ENST00000339362.9	c.879-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19246 AN: 148854 Hom.: 1936 Cov.: 29

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.0656

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.000972

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0960

GnomAD3 exomes AF: 0.0935 AC: 8688 AN: 92886 Hom.: 555 AF XY: 0.0863 AC XY: 4288 AN XY: 49692

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.0732

Gnomad EAS exome AF: 0.000268

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.0937

Gnomad OTH exome AF: 0.0778

GnomAD4 exome AF: 0.0760 AC: 97030 AN: 1277070 Hom.: 3486 Cov.: 32 AF XY: 0.0742 AC XY: 46665 AN XY: 628914

Gnomad4 AFR exome AF: 0.273

Gnomad4 AMR exome AF: 0.0488

Gnomad4 ASJ exome AF: 0.0587

Gnomad4 EAS exome AF: 0.000262

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.0761

Gnomad4 OTH exome AF: 0.0754

GnomAD4 genome AF: 0.129 AC: 19251 AN: 148952 Hom.: 1935 Cov.: 29 AF XY: 0.128 AC XY: 9269 AN XY: 72612

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.000974

Gnomad4 SAS AF: 0.0136

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0772

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0935 Hom.: 175

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

NEO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.12
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

Publications

LitVar

Other links and lift over

dbSNP: rs8035499; hg19: chr15-73428224;