2-186640975-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_002210.5(ITGAV):c.956+8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,565,206 control chromosomes in the GnomAD database, including 32 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 0.0083 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (12 hom.)
• Consequence: ITGAV NM_002210.5 splice_region, intron
• Scores: Splicing: ADA: 0.005768
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-186640975-T-A is Benign according to our data. Variant chr2-186640975-T-A is described in ClinVar as [Benign]. Clinvar id is 785019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00829 (1256/151546) while in subpopulation AFR AF= 0.0292 (1206/41362). AF 95% confidence interval is 0.0278. There are 20 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1259 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAV	NM_002210.5	c.956+8T>A		splice_region_variant, intron_variant		ENST00000261023.8
ITGAV	NM_001144999.3	c.818+8T>A		splice_region_variant, intron_variant
ITGAV	NM_001145000.3	c.848+8T>A		splice_region_variant, intron_variant
ITGAV	XM_047444225.1	c.113+8T>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAV	ENST00000261023.8	c.956+8T>A		splice_region_variant, intron_variant		1	NM_002210.5	P2

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1259 AN: 151434 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00234 AC: 449 AN: 192274 Hom.: 4 AF XY: 0.00174 AC XY: 180 AN XY: 103592

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000267

Gnomad SAS exome AF: 0.0000421

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.000844

GnomAD4 exome AF: 0.000808 AC: 1142 AN: 1413660 Hom.: 12 Cov.: 27 AF XY: 0.000705 AC XY: 495 AN XY: 701754

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000176

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00829 AC: 1256 AN: 151546 Hom.: 20 Cov.: 32 AF XY: 0.00793 AC XY: 587 AN XY: 74040

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.00237

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00266 Hom.: 2

Bravo AF: 0.00955

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.9
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0058
dbscSNV1_RF	Benign	0.036
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: rs61765181; hg19: chr2-187505702;