rs11895564

Variant names:

• chr2-172475080-G-A
• rs11895564
• NM_001394928.1:c.1255G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:4
• Conservation: PhyloP100: 3.21
• Publications: 46 publications found

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]

ITGA6-AS1 (HGNC:40308): (ITGA6 antisense RNA 1)

PDK1-AS1 (HGNC:40441): (PDK1 and ITGA6 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 332360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ITGA6	NM_001394928.1	c.1255G>A	p.Ala419Thr	missense_variant	Exon 8 of 26	ENST00000442250.6	NP_001381857.1
ITGA6	NM_000210.4	c.1138G>A	p.Ala380Thr	missense_variant	Exon 7 of 26	ENST00000684293.1	NP_000201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA6	ENST00000442250.6	c.1255G>A	p.Ala419Thr	missense_variant	Exon 8 of 26	5	NM_001394928.1	ENSP00000406694.1
ITGA6	ENST00000684293.1	c.1138G>A	p.Ala380Thr	missense_variant	Exon 7 of 26		NM_000210.4	ENSP00000508249.1

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

GnomAD2 exomes AF: 0.279 AC: 70204 AN: 251350 AF XY: 0.283

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 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

African (AFR) AF: 0.333 AC: 10991 AN: 33032

American (AMR) AF: 0.264 AC: 11795 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8925 AN: 25996

East Asian (EAS) AF: 0.108 AC: 4272 AN: 39668

South Asian (SAS) AF: 0.310 AC: 26592 AN: 85808

European-Finnish (FIN) AF: 0.268 AC: 14302 AN: 53402

Middle Eastern (MID) AF: 0.328 AC: 1878 AN: 5732

European-Non Finnish (NFE) AF: 0.298 AC: 325350 AN: 1092840

Other (OTH) AF: 0.286 AC: 17046 AN: 59700

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

African (AFR) AF: 0.334 AC: 13882 AN: 41516

American (AMR) AF: 0.261 AC: 3997 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1181 AN: 3468

East Asian (EAS) AF: 0.0981 AC: 508 AN: 5180

South Asian (SAS) AF: 0.300 AC: 1448 AN: 4830

European-Finnish (FIN) AF: 0.266 AC: 2818 AN: 10586

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.297 AC: 20209 AN: 67980

Other (OTH) AF: 0.286 AC: 605 AN: 2116

Alfa AF: 0.299 Hom.: 34913

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22189006) -

Junctional epidermolysis bullosa with pyloric atresia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.30	.;.;T;.;.
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
MutationAssessor	Benign	1.9	.;.;L;.;.
PhyloP100		3.2
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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