rs1574028

Positions:

• chr2-172469112-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001394928.1(ITGA6):​c.388-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,613,436 control chromosomes in the GnomAD database, including 6,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (425 hom., cov: 32)
  • Exomes 𝑓: 0.087 (5936 hom.)
• Consequence: ITGA6 NM_001394928.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0790

Genes affected

ITGA6 (HGNC:6142): (integrin subunit alpha 6) 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 in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 6 subunit. This subunit may associate with a beta 1 or beta 4 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. The alpha 6 beta 4 integrin may promote tumorigenesis, while the alpha 6 beta 1 integrin may negatively regulate erbB2/HER2 signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-172469112-C-A is Benign according to our data. Variant chr2-172469112-C-A is described in ClinVar as [Benign]. Clinvar id is 332358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA6	NM_000210.4	c.388-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000684293.1
ITGA6	NM_001394928.1	c.388-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000442250.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA6	ENST00000442250.6	c.388-13C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001394928.1
ITGA6	ENST00000684293.1	c.388-13C>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000210.4	P3

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9720 AN: 152102 Hom.: 426 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0179

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.0656

GnomAD3 exomes AF: 0.0786 AC: 19767 AN: 251334 Hom.: 1031 AF XY: 0.0768 AC XY: 10436 AN XY: 135840

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0156

Gnomad SAS exome AF: 0.0587

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0856

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0866 AC: 126614 AN: 1461218 Hom.: 5936 Cov.: 32 AF XY: 0.0855 AC XY: 62143 AN XY: 726964

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0161

Gnomad4 SAS exome AF: 0.0588

Gnomad4 FIN exome AF: 0.0584

Gnomad4 NFE exome AF: 0.0926

Gnomad4 OTH exome AF: 0.0832

GnomAD4 genome AF: 0.0639 AC: 9723 AN: 152218 Hom.: 425 Cov.: 32 AF XY: 0.0630 AC XY: 4686 AN XY: 74424

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0181

Gnomad4 SAS AF: 0.0571

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0854

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0838 Hom.: 426

Bravo AF: 0.0672

Asia WGS AF: 0.0400 AC: 141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Junctional epidermolysis bullosa with pyloric atresia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.9
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1574028; hg19: chr2-173333840;