rs2298033

chr10-15607711-G-A

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.1730C>T(p.Ser577Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,613,792 control chromosomes in the GnomAD database, including 867 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.028 (115 hom., cov: 32)
  • Exomes 𝑓: 0.022 (752 hom.)
• Consequence: ITGA8 NM_003638.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.40

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=0.0025519729).
• BP6: Variant 10-15607711-G-A is Benign according to our data. Variant chr10-15607711-G-A is described in ClinVar as [Benign]. Clinvar id is 1238988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-15607711-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA8	NM_003638.3	c.1730C>T	p.Ser577Phe	missense_variant	17/30	ENST00000378076.4
ITGA8	NM_001291494.2	c.1685C>T	p.Ser562Phe	missense_variant	16/29
ITGA8	XM_011519752.3	c.1730C>T	p.Ser577Phe	missense_variant	17/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA8	ENST00000378076.4	c.1730C>T	p.Ser577Phe	missense_variant	17/30	1	NM_003638.3	P1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4280 AN: 152120 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0829

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0344 AC: 8642 AN: 251030 Hom.: 315 AF XY: 0.0310 AC XY: 4209 AN XY: 135638

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0592

Gnomad ASJ exome AF: 0.00895

Gnomad EAS exome AF: 0.0764

Gnomad SAS exome AF: 0.00875

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0215 AC: 31491 AN: 1461554 Hom.: 752 Cov.: 31 AF XY: 0.0207 AC XY: 15087 AN XY: 727106

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.00880

Gnomad4 EAS exome AF: 0.0927

Gnomad4 SAS exome AF: 0.00763

Gnomad4 FIN exome AF: 0.0946

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0281 AC: 4285 AN: 152238 Hom.: 115 Cov.: 32 AF XY: 0.0314 AC XY: 2337 AN XY: 74414

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0833

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0191 Hom.: 95

Bravo AF: 0.0240

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.0322 AC: 3907

Asia WGS AF: 0.0540 AC: 188 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 23153507) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.14
Sift	Benign	0.053	T
Sift4G	Uncertain	0.055	T
Polyphen		0.43	B
Vest4		0.14
MPC		0.15
ClinPred		0.016	T
GERP RS		4.9
Varity_R		0.059
gMVP		0.43

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: rs2298033; hg19: chr10-15649710; COSMIC: COSV65229365; COSMIC: COSV65229365;