rs7895372

Variant names:

• chr10-15677622-C-G
• rs7895372
• NM_003638.3:c.646G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.01
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• renal hypodysplasia/aplasia 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 776499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003638.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	NM_003638.3	MANE Select	c.646G>C	p.Val216Leu	missense	Exon 6 of 30	NP_003629.2
	ITGA8	NM_001291494.2		c.646G>C	p.Val216Leu	missense	Exon 6 of 29	NP_001278423.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	ENST00000378076.4	TSL:1 MANE Select	c.646G>C	p.Val216Leu	missense	Exon 6 of 30	ENSP00000367316.3

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

GnomAD2 exomes AF: 0.00751 AC: 1884 AN: 250848 AF XY: 0.00528

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 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

African (AFR) AF: 0.0988 AC: 3296 AN: 33354

American (AMR) AF: 0.00580 AC: 259 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39644

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00972 AC: 56 AN: 5760

European-Non Finnish (NFE) AF: 0.000133 AC: 148 AN: 1111674

Other (OTH) AF: 0.00600 AC: 362 AN: 60346

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

African (AFR) AF: 0.0969 AC: 4022 AN: 41504

American (AMR) AF: 0.00989 AC: 151 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67998

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.0
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
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7895372; hg19: chr10-15719621;