NM_001394928.1:c.2905G>A

Variant names:

• chr2-172491230-G-A
• rs10209072
• NM_001394928.1:c.2905G>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.2905G>A​(p.Val969Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,605,338 control chromosomes in the GnomAD database, including 440 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (216 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (224 hom.)
• Consequence: ITGA6 NM_001394928.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.06
• Publications: 9 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]

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015976727).
• BP6: Variant 2-172491230-G-A is Benign according to our data. Variant chr2-172491230-G-A is described in ClinVar as Benign. ClinVar VariationId is 332379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394928.1. 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.2905G>A	p.Val969Met	missense	Exon 23 of 26	NP_001381857.1	P23229-1
	ITGA6	NM_000210.4	MANE Select	c.2788G>A	p.Val930Met	missense	Exon 22 of 26	NP_000201.2	P23229-2
	ITGA6	NM_001079818.3		c.2788G>A	p.Val930Met	missense	Exon 22 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.2905G>A	p.Val969Met	missense	Exon 23 of 26	ENSP00000406694.1	P23229-1
	ITGA6	ENST00000684293.1	MANE Select	c.2788G>A	p.Val930Met	missense	Exon 22 of 26	ENSP00000508249.1	P23229-2
	ITGA6	ENST00000264107.12	TSL:1	c.2743G>A	p.Val915Met	missense	Exon 22 of 26	ENSP00000264107.8	A0A8C8KBL6

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4580 AN: 152084 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00849 AC: 2133 AN: 251342 AF XY: 0.00609

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00319 AC: 4640 AN: 1453136 Hom.: 224 Cov.: 28 AF XY: 0.00275 AC XY: 1992 AN XY: 723636

African (AFR) AF: 0.108 AC: 3582 AN: 33184

American (AMR) AF: 0.00577 AC: 258 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86086

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.00608 AC: 35 AN: 5752

European-Non Finnish (NFE) AF: 0.000262 AC: 289 AN: 1104170

Other (OTH) AF: 0.00741 AC: 445 AN: 60090

GnomAD4 genome AF: 0.0302 AC: 4599 AN: 152202 Hom.: 216 Cov.: 32 AF XY: 0.0286 AC XY: 2129 AN XY: 74404

African (AFR) AF: 0.106 AC: 4409 AN: 41502

American (AMR) AF: 0.00843 AC: 129 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0114 Hom.: 181

Bravo AF: 0.0351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.109 AC: 481

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0103 AC: 1256

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000474

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	0.093
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.054
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.63	P
Vest4		0.23
MPC		0.42
ClinPred		0.0029	T
GERP RS		2.0
Varity_R		0.020
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10209072; hg19: chr2-173355958; COSMIC: COSV51223724; COSMIC: COSV51223724;