rs2507940

Positions:

• chr3-37494493-C-G
• chr3-37494493-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002207.3(ITGA9):​c.545-8C>G 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 0.57 in 1,596,584 control chromosomes in the GnomAD database, including 265,531 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 0.53 (22124 hom., cov: 32)
  • Exomes 𝑓: 0.57 (243407 hom.)
• Consequence: ITGA9 NM_002207.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002356
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.286

Genes affected

ITGA9 (HGNC:6145): (integrin subunit alpha 9) This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane glycoproteins composed of an alpha chain and a beta chain that mediate cell-cell and cell-matrix adhesion. The protein encoded by this gene, when bound to the beta 1 chain, forms an integrin that is a receptor for VCAM1, cytotactin and osteopontin. Expression of this gene has been found to be upregulated in small cell lung cancers. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-37494493-C-G is Benign according to our data. Variant chr3-37494493-C-G is described in ClinVar as [Benign]. Clinvar id is 402987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37494493-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA9	NM_002207.3	c.545-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264741.10	NP_002198.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA9	ENST00000264741.10	c.545-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002207.3	ENSP00000264741	P1
ITGA9	ENST00000422441.5	c.545-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000397258

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80392 AN: 151992 Hom.: 22116 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.531

GnomAD3 exomes AF: 0.569 AC: 141317 AN: 248342 Hom.: 42225 AF XY: 0.558 AC XY: 74845 AN XY: 134200

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.741

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.799

Gnomad SAS exome AF: 0.399

Gnomad FIN exome AF: 0.502

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.574 AC: 829399 AN: 1444474 Hom.: 243407 Cov.: 30 AF XY: 0.567 AC XY: 408074 AN XY: 719362

Gnomad4 AFR exome AF: 0.399

Gnomad4 AMR exome AF: 0.725

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.529 AC: 80429 AN: 152110 Hom.: 22124 Cov.: 32 AF XY: 0.523 AC XY: 38917 AN XY: 74346

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.531

Alfa AF: 0.546 Hom.: 7507

Bravo AF: 0.543

Asia WGS AF: 0.566 AC: 1969 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 57% of total chromosomes in ExAC -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

ITGA9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 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	-0.43
CADD	Benign	8.9
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.048
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

Publications

LitVar

Other links and lift over

dbSNP: rs2507940; hg19: chr3-37535984;