2-172504202-GA-GAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_001394928.1(ITGA6):c.3351dupA(p.Gln1118ThrfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,580,016 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

ITGA6
NM_001394928.1 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 8.72

Publications

6 publications found

Variant links:

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 links:

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

ITGA6-AS1 links:

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

PDK1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0121 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 2-172504202-G-GA is Benign according to our data. Variant chr2-172504202-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225394.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000346 (52/150490) while in subpopulation EAS AF = 0.00765 (39/5100). AF 95% confidence interval is 0.00575. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA6	NM_001394928.1 link	c.3351dupA	p.Gln1118ThrfsTer10	frameshift_variant	Exon 26 of 26	ENST00000442250.6	NP_001381857.1
ITGA6	NM_000210.4 link	c.*142dupA		3_prime_UTR_variant	Exon 26 of 26	ENST00000684293.1	NP_000201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA6	ENST00000442250.6 link	c.3351dupA	p.Gln1118ThrfsTer10	frameshift_variant	Exon 26 of 26	5	NM_001394928.1	ENSP00000406694.1
ITGA6	ENST00000684293.1 link	c.*142dupA		3_prime_UTR_variant	Exon 26 of 26		NM_000210.4	ENSP00000508249.1

Frequencies

GnomAD3 genomes

AF:

0.000346

AC:

AN:

150374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00763

Gnomad SAS

AF:

0.00126

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000798

AC:

160

AN:

200476

AF XY:

0.000774

show subpopulations

Gnomad AFR exome

AF:

0.0000848

Gnomad AMR exome

AF:

0.000527

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00855

Gnomad FIN exome

AF:

0.0000516

Gnomad NFE exome

AF:

0.000137

Gnomad OTH exome

AF:

0.000771

GnomAD4 exome

AF:

0.000283

AC:

405

AN:

1429526

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

215

AN XY:

708480

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32604

American (AMR)

AF:

0.000448

AC:

AN:

40138

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25480

East Asian (EAS)

AF:

0.00730

AC:

281

AN:

38512

South Asian (SAS)

AF:

0.000270

AC:

AN:

81618

European-Finnish (FIN)

AF:

0.0000388

AC:

AN:

51592

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

1094640

Other (OTH)

AF:

0.000490

AC:

AN:

59234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000346

AC:

AN:

150490

Hom.:

Cov.:

AF XY:

0.000449

AC XY:

AN XY:

73466

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41026

American (AMR)

AF:

0.000132

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00765

AC:

AN:

5100

South Asian (SAS)

AF:

0.00127

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

67560

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epidermolysis bullosa, junctional 6, with pyloric atresia

Uncertain:1Benign:1

Nov 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa with pyloric atresia

Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.7

Mutation Taster

=20/180

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over