17-50076642-G-C

Variant names:

• chr17-50076642-G-C
• rs140781106
• NM_002204.4:c.1883G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002204.4(ITGA3):​c.1883G>C​(p.Arg628Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R628Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITGA3 NM_002204.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.437
• Publications: 8 publications found

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]

ITGA3 Gene-Disease associations (from GenCC):

• epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50076642-G-C is Pathogenic according to our data. Variant chr17-50076642-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 35572.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002204.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA3	NM_002204.4	MANE Select	c.1883G>C	p.Arg628Pro	missense	Exon 14 of 26	NP_002195.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA3	ENST00000320031.13	TSL:1 MANE Select	c.1883G>C	p.Arg628Pro	missense	Exon 14 of 26	ENSP00000315190.8
	ITGA3	ENST00000007722.11	TSL:5	c.1883G>C	p.Arg628Pro	missense	Exon 14 of 25	ENSP00000007722.7
	ITGA3	ENST00000506827.1	TSL:3	c.17G>C	p.Arg6Pro	missense	Exon 1 of 7	ENSP00000426142.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247364 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726986

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome Pathogenic:1

Apr 19, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nephrotic syndrome Pathogenic:1

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.44
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.20
Sift	Benign	0.055	T
Sift4G	Benign	0.061	T
Polyphen		0.82	P
Vest4		0.74
MutPred		0.64		Loss of MoRF binding (P = 0.0379)
MVP		0.60
MPC		1.1
ClinPred		0.57	D
GERP RS		-0.94
PromoterAI		-0.012	Neutral
Varity_R		0.42
gMVP		0.86
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs140781106; hg19: chr17-48154006;