2-186590440-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002210.5(ITGAV):c.102C>G(p.Asp34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,460,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ITGAV NM_002210.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.240

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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAV	NM_002210.5	c.102C>G	p.Asp34Glu	missense_variant	1/30	ENST00000261023.8
ITGAV	NM_001145000.3	c.102C>G	p.Asp34Glu	missense_variant	1/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAV	ENST00000261023.8	c.102C>G	p.Asp34Glu	missense_variant	1/30	1	NM_002210.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248532 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1460800 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726646

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

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

Oct 26, 2022

The c.102C>G (p.D34E) alteration is located in exon 1 (coding exon 1) of the ITGAV gene. This alteration results from a C to G substitution at nucleotide position 102, causing the aspartic acid (D) at amino acid position 34 to be replaced by a glutamic acid (E). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.98	D;P
Vest4		0.72
MutPred		0.80		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.94
MPC		0.61
ClinPred		0.97	D
GERP RS		-2.1
Varity_R		0.67
gMVP		0.79

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: rs747523789; hg19: chr2-187455167;