2-186633380-T-C

Variant names:

• chr2-186633380-T-C
• rs9333289
• NM_002210.5:c.631+6T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002210.5(ITGAV):​c.631+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,539,620 control chromosomes in the GnomAD database, including 55,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.21 (4059 hom., cov: 30)
  • Exomes 𝑓: 0.26 (51020 hom.)
• Consequence: ITGAV NM_002210.5 splice_region, intron
• Scores: Splicing: ADA: 0.3053
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675
• Publications: 18 publications found

Genes affected

ITGAV (HGNC:6150): (integrin subunit alpha V) The product of this gene belongs to the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of an alpha subunit and a beta subunit that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha V subunit. This subunit associates with beta 1, beta 3, beta 5, beta 6 and beta 8 subunits. The heterodimer consisting of alpha V and beta 3 subunits is also known as the vitronectin receptor. This integrin may regulate angiogenesis and cancer progression. Alternative splicing results in multiple transcript variants. Note that the integrin alpha 5 and integrin alpha V subunits are encoded by distinct genes. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGAV	NM_002210.5	c.631+6T>C		splice_region_variant, intron_variant	Intron 6 of 29	ENST00000261023.8	NP_002201.2
ITGAV	NM_001145000.3	c.524-2702T>C		intron_variant	Intron 4 of 27		NP_001138472.2
ITGAV	NM_001144999.3	c.493+6T>C		splice_region_variant, intron_variant	Intron 6 of 29		NP_001138471.2
ITGAV	XM_047444225.1	c.-213+6T>C		splice_region_variant, intron_variant	Intron 2 of 25		XP_047300181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGAV	ENST00000261023.8	c.631+6T>C		splice_region_variant, intron_variant	Intron 6 of 29	1	NM_002210.5	ENSP00000261023.3

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31805 AN: 151294 Hom.: 4057 Cov.: 30

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.250 AC: 61815 AN: 247166 AF XY: 0.258

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.265 AC: 367556 AN: 1388214 Hom.: 51020 Cov.: 21 AF XY: 0.267 AC XY: 185345 AN XY: 693258

African (AFR) AF: 0.0436 AC: 1417 AN: 32516

American (AMR) AF: 0.246 AC: 10765 AN: 43790

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7476 AN: 24796

East Asian (EAS) AF: 0.107 AC: 4174 AN: 39076

South Asian (SAS) AF: 0.288 AC: 23224 AN: 80522

European-Finnish (FIN) AF: 0.242 AC: 12363 AN: 51070

Middle Eastern (MID) AF: 0.311 AC: 1716 AN: 5524

European-Non Finnish (NFE) AF: 0.277 AC: 291917 AN: 1053572

Other (OTH) AF: 0.253 AC: 14504 AN: 57348

GnomAD4 genome AF: 0.210 AC: 31798 AN: 151406 Hom.: 4059 Cov.: 30 AF XY: 0.210 AC XY: 15503 AN XY: 73964

African (AFR) AF: 0.0521 AC: 2159 AN: 41438

American (AMR) AF: 0.243 AC: 3682 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1085 AN: 3464

East Asian (EAS) AF: 0.133 AC: 688 AN: 5172

South Asian (SAS) AF: 0.298 AC: 1425 AN: 4784

European-Finnish (FIN) AF: 0.237 AC: 2437 AN: 10296

Middle Eastern (MID) AF: 0.293 AC: 85 AN: 290

European-Non Finnish (NFE) AF: 0.287 AC: 19461 AN: 67774

Other (OTH) AF: 0.229 AC: 479 AN: 2096

Alfa AF: 0.259 Hom.: 14196

Bravo AF: 0.202

Asia WGS AF: 0.207 AC: 719 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.84
PhyloP100		0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.010		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: rs9333289; hg19: chr2-187498107; COSMIC: COSV53710438;