10-15607699-T-G

Position:

• chr10-15607699-T-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.1742A>C​(p.Gln581Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 1,613,564 control chromosomes in the GnomAD database, including 5,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 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 0.063 (393 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5480 hom.)
• Consequence: ITGA8 NM_003638.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0950

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=0.0030740798).
• BP6: Variant 10-15607699-T-G is Benign according to our data. Variant chr10-15607699-T-G is described in ClinVar as [Benign]. Clinvar id is 1183844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA8	NM_003638.3	c.1742A>C	p.Gln581Pro	missense_variant	17/30	ENST00000378076.4	NP_003629.2
ITGA8	NM_001291494.2	c.1697A>C	p.Gln566Pro	missense_variant	16/29		NP_001278423.1
ITGA8	XM_011519752.3	c.1742A>C	p.Gln581Pro	missense_variant	17/24		XP_011518054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA8	ENST00000378076.4	c.1742A>C	p.Gln581Pro	missense_variant	17/30	1	NM_003638.3	ENSP00000367316.3

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9583 AN: 152166 Hom.: 393 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0991

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.0702

GnomAD3 exomes AF: 0.0686 AC: 17207 AN: 250954 Hom.: 772 AF XY: 0.0697 AC XY: 9456 AN XY: 135612

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0316

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0933

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0818 AC: 119539 AN: 1461280 Hom.: 5480 Cov.: 31 AF XY: 0.0807 AC XY: 58683 AN XY: 726972

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.0488

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0908

Gnomad4 OTH exome AF: 0.0771

GnomAD4 genome AF: 0.0629 AC: 9586 AN: 152284 Hom.: 393 Cov.: 32 AF XY: 0.0628 AC XY: 4679 AN XY: 74458

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.0682

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0991

Gnomad4 NFE AF: 0.0903

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0830 Hom.: 957

Bravo AF: 0.0583

TwinsUK AF: 0.0941 AC: 349

ALSPAC AF: 0.0880 AC: 339

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.0903 AC: 777

ExAC AF: 0.0686 AC: 8330

Asia WGS AF: 0.0150 AC: 54 AN: 3478

EpiCase AF: 0.0930

EpiControl AF: 0.0961

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.7
DANN	Benign	0.76
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.073
Sift	Benign	0.031	D
Sift4G	Benign	0.089	T
Polyphen		0.55	P
Vest4		0.22
MPC		0.19
ClinPred		0.052	T
GERP RS		-2.0
Varity_R		0.44
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

Other links and lift over

dbSNP: rs9333269; hg19: chr10-15649698; COSMIC: COSV65226526; COSMIC: COSV65226526;