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_000210.4(ITGA6):​c.1138G>A​(p.Ala380Thr) 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. A380A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (6806 hom., cov: 33)
  • Exomes 𝑓: 0.29 (63327 hom.)
• Consequence: ITGA6 NM_000210.4 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000210.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA6	NM_001394928.1	MANE Plus Clinical	c.1255G>A	p.Ala419Thr	missense	Exon 8 of 26	NP_001381857.1	P23229-1
	ITGA6	NM_000210.4	MANE Select	c.1138G>A	p.Ala380Thr	missense	Exon 7 of 26	NP_000201.2	P23229-2
	ITGA6	NM_001079818.3		c.1138G>A	p.Ala380Thr	missense	Exon 7 of 25	NP_001073286.1	P23229-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA6	ENST00000442250.6	TSL:5 MANE Plus Clinical	c.1255G>A	p.Ala419Thr	missense	Exon 8 of 26	ENSP00000406694.1	P23229-1
	ITGA6	ENST00000684293.1	MANE Select	c.1138G>A	p.Ala380Thr	missense	Exon 7 of 26	ENSP00000508249.1	P23229-2
	ITGA6	ENST00000264107.12	TSL:1	c.1138G>A	p.Ala380Thr	missense	Exon 7 of 26	ENSP00000264107.8	A0A8C8KBL6

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Junctional epidermolysis bullosa with pyloric atresia (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.14	T
Sift4G	Benign	0.28	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;