17-50056581-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002204.4(ITGA3):c.142C>T(p.Pro48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 1,437,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P48P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: ITGA3 NM_002204.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

ITGA3 (HGNC:6139): (integrin subunit alpha 3) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function as cell surface adhesion molecules. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 3 subunit. This subunit joins with a beta 1 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. Expression of this gene may be correlated with breast cancer metastasis. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1414265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA3	NM_002204.4	c.142C>T	p.Pro48Ser	missense_variant	1/26	ENST00000320031.13
ITGA3	XM_005257308.3	c.142C>T	p.Pro48Ser	missense_variant	1/24
ITGA3	XM_047435922.1	c.142C>T	p.Pro48Ser	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA3	ENST00000320031.13	c.142C>T	p.Pro48Ser	missense_variant	1/26	1	NM_002204.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000194 AC: 4 AN: 206320 Hom.: 0 AF XY: 0.00000887 AC XY: 1 AN XY: 112724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 7 AN: 1437714 Hom.: 0 Cov.: 31 AF XY: 0.00000421 AC XY: 3 AN XY: 713038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000966

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 48 of the ITGA3 protein (p.Pro48Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ITGA3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGA3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.29
Sift	Benign	0.12	T;T
Sift4G	Benign	0.074	T;T
Polyphen		0.0050	B;P
Vest4		0.16
MutPred		0.29		Gain of disorder (P = 0.087);Gain of disorder (P = 0.087);
MVP		0.86
MPC		0.67
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.23
gMVP		0.44

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: rs768529626; hg19: chr17-48133945;