10-15519316-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_003638.3(ITGA8):c.3079G>A(p.Ala1027Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000463 in 1,613,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

ITGA8
NM_003638.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.88

Variant links:

Genes affected

ITGA8 (HGNC:6144): (integrin subunit alpha 8) Integrins are heterodimeric transmembrane receptor proteins that mediate numerous cellular processes including cell adhesion, cytoskeletal rearrangement, and activation of cell signaling pathways. Integrins are composed of alpha and beta subunits. This gene encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1 protein. The encoded protein is a single-pass type 1 membrane protein that contains multiple FG-GAP repeats. This repeat is predicted to fold into a beta propeller structure. This gene regulates the recruitment of mesenchymal cells into epithelial structures, mediates cell-cell interactions, and regulates neurite outgrowth of sensory and motor neurons. The integrin alpha8beta1 protein thus plays an important role in wound-healing and organogenesis. Mutations in this gene have been associated with renal hypodysplasia/aplasia-1 (RHDA1) and with several animal models of chronic kidney disease. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2014]

ITGA8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029220253).

BP6

Variant 10-15519316-C-T is Benign according to our data. Variant chr10-15519316-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2065706.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000533 (81/152072) while in subpopulation NFE AF= 0.000794 (54/68020). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA8	NM_003638.3 linkuse as main transcript	c.3079G>A	p.Ala1027Thr	missense_variant	29/30	ENST00000378076.4
ITGA8	NM_001291494.2 linkuse as main transcript	c.3034G>A	p.Ala1012Thr	missense_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA8	ENST00000378076.4 linkuse as main transcript	c.3079G>A	p.Ala1027Thr	missense_variant	29/30	1	NM_003638.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000669

AC:

168

AN:

251100

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00306

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000456

AC:

666

AN:

1461388

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00345

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000533

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000610

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.3079G>A (p.A1027T) alteration is located in exon 29 (coding exon 29) of the ITGA8 gene. This alteration results from a G to A substitution at nucleotide position 3079, causing the alanine (A) at amino acid position 1027 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.073

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

M_CAP

Benign

0.020

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.094

Sift

Uncertain

0.017

Sift4G

Benign

0.14

Polyphen

0.10

Vest4

0.38

MVP

0.72

MPC

0.093

ClinPred

0.076

GERP RS

4.6

Varity_R

0.25

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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