rs11895564

chr2-172475080-G-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.1255G>A(p.Ala419Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,593,052 control chromosomes in the GnomAD database, including 70,133 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A419A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (6806 hom., cov: 33)
  • Exomes 𝑓: 0.29 (63327 hom.)
• Consequence: ITGA6 NM_001394928.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.21

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 (MetaRNN=0.0016584992).
• BP6: Variant 2-172475080-G-A is Benign according to our data. Variant chr2-172475080-G-A is described in ClinVar as [Benign]. Clinvar id is 332360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-172475080-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA6	NM_001394928.1	c.1255G>A	p.Ala419Thr	missense_variant	8/26	ENST00000442250.6
ITGA6	NM_000210.4	c.1138G>A	p.Ala380Thr	missense_variant	7/26	ENST00000684293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA6	ENST00000442250.6	c.1255G>A	p.Ala419Thr	missense_variant	8/26	5	NM_001394928.1
ITGA6	ENST00000684293.1	c.1138G>A	p.Ala380Thr	missense_variant	7/26		NM_000210.4	P3

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45041 AN: 152050 Hom.: 6809 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.279 AC: 70204 AN: 251350 Hom.: 10368 AF XY: 0.283 AC XY: 38436 AN XY: 135850

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.0881

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.292 AC: 421151 AN: 1440884 Hom.: 63327 Cov.: 29 AF XY: 0.294 AC XY: 210879 AN XY: 717980

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.268

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.296 AC: 45061 AN: 152168 Hom.: 6806 Cov.: 33 AF XY: 0.294 AC XY: 21893 AN XY: 74384

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.0981

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.286

Alfa AF: 0.300 Hom.: 18072

Bravo AF: 0.298

TwinsUK AF: 0.301 AC: 1116

ALSPAC AF: 0.299 AC: 1151

ESP6500AA AF: 0.342 AC: 1505

ESP6500EA AF: 0.298 AC: 2560

ExAC AF: 0.281 AC: 34109

Asia WGS AF: 0.208 AC: 724 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.301

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	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22189006) -
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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.000047	P;P;P;P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.86	.;P;.;.;.
Vest4		0.26
MPC		0.60
ClinPred		0.0077	T
GERP RS		4.5
Varity_R		0.052
gMVP		0.83

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: rs11895564; hg19: chr2-173339808; COSMIC: COSV51226899; COSMIC: COSV51226899;