2-172475080-G-A

Position:

chr2-172475080-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1255G>A	p.Ala419Thr	missense_variant	8/26	ENST00000442250.6
ITGA6	NM_000210.4 linkuse as main transcript	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 linkuse as main transcript	c.1255G>A	p.Ala419Thr	missense_variant	8/26	5	NM_001394928.1		P23229-1
ITGA6	ENST00000684293.1 linkuse as main transcript	c.1138G>A	p.Ala380Thr	missense_variant	7/26		NM_000210.4	P3	P23229-2

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

45041

AN:

152050

Hom.:

6809

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.294

AC XY:

210879

AN XY:

717980

show subpopulations

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.:

AF XY:

0.294

AC XY:

21893

AN XY:

74384

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;.;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;.;L;.;.

MutationTaster

Benign

0.000047

P;P;P;P;P;P

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over