2-186602133-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002210.5(ITGAV):c.298A>G(p.Ile100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,608,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: ITGAV NM_002210.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10358402).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAV	NM_002210.5	c.298A>G	p.Ile100Val	missense_variant	2/30	ENST00000261023.8
ITGAV	NM_001145000.3	c.298A>G	p.Ile100Val	missense_variant	2/28
ITGAV	NM_001144999.3	c.160A>G	p.Ile54Val	missense_variant	2/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAV	ENST00000261023.8	c.298A>G	p.Ile100Val	missense_variant	2/30	1	NM_002210.5	P2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000693 AC: 17 AN: 245290 Hom.: 0 AF XY: 0.0000756 AC XY: 10 AN XY: 132358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000618 AC: 90 AN: 1456156 Hom.: 0 Cov.: 30 AF XY: 0.0000663 AC XY: 48 AN XY: 724046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.298A>G (p.I100V) alteration is located in exon 2 (coding exon 2) of the ITGAV gene. This alteration results from a A to G substitution at nucleotide position 298, causing the isoleucine (I) at amino acid position 100 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.40	N;N;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.76	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.072	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.27
MVP		0.82
MPC		0.15
ClinPred		0.044	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs201231113; hg19: chr2-187466860; COSMIC: COSV53721051;