NM_003638.3:c.2981T>C

Variant names:

Variant summary

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

The NM_003638.3(ITGA8):c.2981T>C(p.Val994Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,439,102 control chromosomes in the GnomAD database, including 702,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.96 ( 70595 hom., cov: 32)

Exomes 𝑓: 0.99 ( 631590 hom. )

Consequence

ITGA8
NM_003638.3 missense, splice_region

Scores

Splicing: ADA: 0.00005962

Clinical Significance

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

Conservation

PhyloP100: 3.05

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7617638E-6).

BP6

Variant 10-15531051-A-G is Benign according to our data. Variant chr10-15531051-A-G is described in ClinVar as [Benign]. Clinvar id is 1290122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA8	NM_003638.3 link	c.2981T>C	p.Val994Ala	missense_variant, splice_region_variant	Exon 28 of 30	ENST00000378076.4	NP_003629.2	P53708B4DN28
ITGA8	NM_001291494.2 link	c.2936T>C	p.Val979Ala	missense_variant, splice_region_variant	Exon 27 of 29		NP_001278423.1	B4DN28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA8	ENST00000378076.4 link	c.2981T>C	p.Val994Ala	missense_variant, splice_region_variant	Exon 28 of 30	1	NM_003638.3	ENSP00000367316.3		P53708

Frequencies

GnomAD3 genomes

AF:

0.961

AC:

146273

AN:

152182

Hom.:

70539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.896

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.984

Gnomad ASJ

AF:

0.986

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.981

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.968

GnomAD3 exomes

AF:

0.973

AC:

213956

AN:

219856

Hom.:

104569

AF XY:

0.976

AC XY:

116513

AN XY:

119350

show subpopulations

Gnomad AFR exome

AF:

0.890

Gnomad AMR exome

AF:

0.994

Gnomad ASJ exome

AF:

0.987

Gnomad EAS exome

AF:

0.773

Gnomad SAS exome

AF:

0.986

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.989

GnomAD4 exome

AF:

0.990

AC:

1274075

AN:

1286802

Hom.:

631590

Cov.:

AF XY:

0.990

AC XY:

641206

AN XY:

647400

show subpopulations

Gnomad4 AFR exome

AF:

0.887

Gnomad4 AMR exome

AF:

0.993

Gnomad4 ASJ exome

AF:

0.988

Gnomad4 EAS exome

AF:

0.831

Gnomad4 SAS exome

AF:

0.987

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.979

GnomAD4 genome

AF:

0.961

AC:

146389

AN:

152300

Hom.:

70595

Cov.:

AF XY:

0.962

AC XY:

71609

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.896

Gnomad4 AMR

AF:

0.984

Gnomad4 ASJ

AF:

0.986

Gnomad4 EAS

AF:

0.785

Gnomad4 SAS

AF:

0.982

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.999

Gnomad4 OTH

AF:

0.969

Alfa

AF:

0.990

Hom.:

152503

Bravo

AF:

0.955

TwinsUK

AF:

0.999

AC:

3706

ALSPAC

AF:

0.998

AC:

3848

ESP6500AA

AF:

0.895

AC:

3945

ESP6500EA

AF:

0.999

AC:

8590

ExAC

AF:

0.972

AC:

118061

Asia WGS

AF:

0.907

AC:

3150

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypodysplasia/aplasia 1

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.050

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.036

MetaRNN

Benign

0.0000018

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.39

REVEL

Benign

0.065

Sift

Benign

1.0

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.017

MPC

0.082

ClinPred

0.0018

GERP RS

4.7

Varity_R

0.034

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000060

dbscSNV1_RF

Benign

0.13

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