rs7895372

Positions:

• chr10-15677622-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003638.3(ITGA8):​c.646G>C​(p.Val216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,613,238 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V216A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (185 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (184 hom.)
• Consequence: ITGA8 NM_003638.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024095178).
• BP6: Variant 10-15677622-C-G is Benign according to our data. Variant chr10-15677622-C-G is described in ClinVar as [Benign]. Clinvar id is 776499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA8	NM_003638.3	c.646G>C	p.Val216Leu	missense_variant	6/30	ENST00000378076.4
ITGA8	NM_001291494.2	c.646G>C	p.Val216Leu	missense_variant	6/29
ITGA8	XM_011519752.3	c.646G>C	p.Val216Leu	missense_variant	6/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA8	ENST00000378076.4	c.646G>C	p.Val216Leu	missense_variant	6/30	1	NM_003638.3	P1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4213 AN: 152060 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00990

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00751 AC: 1884 AN: 250848 Hom.: 80 AF XY: 0.00528 AC XY: 716 AN XY: 135586

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00287 AC: 4197 AN: 1461060 Hom.: 184 Cov.: 29 AF XY: 0.00248 AC XY: 1802 AN XY: 726854

Gnomad4 AFR exome AF: 0.0988

Gnomad4 AMR exome AF: 0.00580

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00600

GnomAD4 genome AF: 0.0278 AC: 4233 AN: 152178 Hom.: 185 Cov.: 32 AF XY: 0.0264 AC XY: 1963 AN XY: 74412

Gnomad4 AFR AF: 0.0969

Gnomad4 AMR AF: 0.00989

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00508 Hom.: 31

Bravo AF: 0.0331

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.103 AC: 453

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00930 AC: 1129

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.34
MutPred		0.35		Gain of sheet (P = 0.1208);
MVP		0.49
MPC		0.073
ClinPred		0.0079	T
GERP RS		4.6
Varity_R		0.039
gMVP		0.47

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

Other links and lift over

dbSNP: rs7895372; hg19: chr10-15719621;