10-15531051-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin 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:3
• Conservation: PhyloP100: 3.05

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]

ACMG classification

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/exons	MANE	UniProt
ITGA8	NM_003638.3	c.2981T>C	p.Val994Ala	missense_variant, splice_region_variant	28/30	ENST00000378076.4
ITGA8	NM_001291494.2	c.2936T>C	p.Val979Ala	missense_variant, splice_region_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA8	ENST00000378076.4	c.2981T>C	p.Val994Ala	missense_variant, splice_region_variant	28/30	1	NM_003638.3	P1

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146273 AN: 152182 Hom.: 70539 Cov.: 32

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

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.: 18 AF XY: 0.990 AC XY: 641206 AN XY: 647400

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.: 32 AF XY: 0.962 AC XY: 71609 AN XY: 74470

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Benign	0.46
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.082
ClinPred		0.0018	T
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

Other links and lift over

dbSNP: rs1041135; hg19: chr10-15573050;