10-15531055-T-C

Variant names:

• chr10-15531055-T-C
• rs9333241
• NM_003638.3:c.2977A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003638.3(ITGA8):​c.2977A>G​(p.Ile993Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,483,740 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: ITGA8 NM_003638.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.97
• Publications: 6 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: G2P, Ambry Genetics, 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=0.002313584).
• BP6: Variant 10-15531055-T-C is Benign according to our data. Variant chr10-15531055-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 779107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00679 (1034/152338) while in subpopulation AFR AF = 0.0232 (966/41572). AF 95% confidence interval is 0.022. There are 6 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	NM_003638.3	MANE Select	c.2977A>G	p.Ile993Val	missense	Exon 28 of 30	NP_003629.2	P53708
	ITGA8	NM_001291494.2		c.2932A>G	p.Ile978Val	missense	Exon 27 of 29	NP_001278423.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	ENST00000378076.4	TSL:1 MANE Select	c.2977A>G	p.Ile993Val	missense	Exon 28 of 30	ENSP00000367316.3	P53708
	ITGA8	ENST00000882526.1		c.2881-11643A>G		intron	N/A	ENSP00000552585.1
	ITGA8	ENST00000967017.1		c.2836-11643A>G		intron	N/A	ENSP00000637076.1

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1032 AN: 152220 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00173 AC: 378 AN: 218654 AF XY: 0.00122

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000288

Gnomad OTH exome AF: 0.000967

GnomAD4 exome AF: 0.000624 AC: 831 AN: 1331402 Hom.: 11 Cov.: 20 AF XY: 0.000493 AC XY: 329 AN XY: 667244

African (AFR) AF: 0.0223 AC: 659 AN: 29492

American (AMR) AF: 0.00175 AC: 62 AN: 35410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24750

East Asian (EAS) AF: 0.00 AC: 0 AN: 37966

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 74978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.000361 AC: 2 AN: 5536

European-Non Finnish (NFE) AF: 0.0000197 AC: 20 AN: 1014206

Other (OTH) AF: 0.00155 AC: 87 AN: 55962

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152338 Hom.: 6 Cov.: 33 AF XY: 0.00651 AC XY: 485 AN XY: 74504

African (AFR) AF: 0.0232 AC: 966 AN: 41572

American (AMR) AF: 0.00353 AC: 54 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00295 Hom.: 11

Bravo AF: 0.00820

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.078
Sift	Benign	0.48	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.53
MPC		0.060
ClinPred		0.0065	T
GERP RS		3.0
Varity_R		0.024
gMVP		0.29
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs9333241; hg19: chr10-15573054; COSMIC: COSV99061943;