2-172427651-G-A

Position:

• chr2-172427651-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001394928.1(ITGA6):​c.-138G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,311,478 control chromosomes in the GnomAD database, including 2,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (251 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2089 hom.)
• Consequence: ITGA6 NM_001394928.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.534

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 2-172427651-G-A is Benign according to our data. Variant chr2-172427651-G-A is described in ClinVar as [Benign]. Clinvar id is 332352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA6	NM_000210.4	c.-138G>A		5_prime_UTR_variant	1/26	ENST00000684293.1	NP_000201.2
ITGA6	NM_001394928.1	c.-138G>A		5_prime_UTR_variant	1/26	ENST00000442250.6	NP_001381857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA6	ENST00000442250.6	c.-138G>A		5_prime_UTR_variant	1/26	5	NM_001394928.1	ENSP00000406694
ITGA6	ENST00000684293.1	c.-138G>A		5_prime_UTR_variant	1/26		NM_000210.4	ENSP00000508249	P3

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6672 AN: 152142 Hom.: 251 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0548 AC: 63536 AN: 1159228 Hom.: 2089 Cov.: 34 AF XY: 0.0550 AC XY: 30670 AN XY: 557422

Gnomad4 AFR exome AF: 0.00623

Gnomad4 AMR exome AF: 0.0616

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.0789

Gnomad4 FIN exome AF: 0.0397

Gnomad4 NFE exome AF: 0.0528

Gnomad4 OTH exome AF: 0.0544

GnomAD4 genome AF: 0.0438 AC: 6676 AN: 152250 Hom.: 251 Cov.: 33 AF XY: 0.0440 AC XY: 3275 AN XY: 74442

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.0517

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.0822

Gnomad4 FIN AF: 0.0374

Gnomad4 NFE AF: 0.0508

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0447 Hom.: 21

Bravo AF: 0.0445

Asia WGS AF: 0.135 AC: 467 AN: 3466

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 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.25
CADD	Benign	18
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs144682022; hg19: chr2-173292379;