rs1041135

Variant names:

• chr10-15531051-A-G
• rs1041135
• NM_003638.3:c.2981T>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.2981T>C​(p.Val994Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,439,102 control chromosomes in the GnomAD database, including 702,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V994I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.96 (70595 hom., cov: 32)
  • Exomes 𝑓: 0.99 (631590 hom.)
• Consequence: ITGA8 NM_003638.3 missense, splice_region
• Scores: Splicing: ADA: 0.00005962
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.05
• Publications: 27 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=1.7617638E-6).
• BP6: Variant 10-15531051-A-G is Benign according to our data. Variant chr10-15531051-A-G is described in ClinVar as Benign. ClinVar VariationId is 1290122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	NM_003638.3	MANE Select	c.2981T>C	p.Val994Ala	missense splice_region	Exon 28 of 30	NP_003629.2	P53708
	ITGA8	NM_001291494.2		c.2936T>C	p.Val979Ala	missense splice_region	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.2981T>C	p.Val994Ala	missense splice_region	Exon 28 of 30	ENSP00000367316.3	P53708
	ITGA8	ENST00000882526.1		c.2881-11639T>C		intron	N/A	ENSP00000552585.1
	ITGA8	ENST00000967017.1		c.2836-11639T>C		intron	N/A	ENSP00000637076.1

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146273 AN: 152182 Hom.: 70539 Cov.: 32

Gnomad AFR AF: 0.896

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.981

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.973 AC: 213956 AN: 219856 AF XY: 0.976

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.987

Gnomad EAS exome AF: 0.773

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.989

GnomAD4 exome AF: 0.990 AC: 1274075 AN: 1286802 Hom.: 631590 Cov.: 18 AF XY: 0.990 AC XY: 641206 AN XY: 647400

African (AFR) AF: 0.887 AC: 25274 AN: 28482

American (AMR) AF: 0.993 AC: 35388 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 24234 AN: 24536

East Asian (EAS) AF: 0.831 AC: 31175 AN: 37508

South Asian (SAS) AF: 0.987 AC: 72971 AN: 73966

European-Finnish (FIN) AF: 1.00 AC: 53079 AN: 53082

Middle Eastern (MID) AF: 0.994 AC: 5399 AN: 5434

European-Non Finnish (NFE) AF: 1.00 AC: 973236 AN: 973676

Other (OTH) AF: 0.979 AC: 53319 AN: 54480

GnomAD4 genome AF: 0.961 AC: 146389 AN: 152300 Hom.: 70595 Cov.: 32 AF XY: 0.962 AC XY: 71609 AN XY: 74470

African (AFR) AF: 0.896 AC: 37224 AN: 41538

American (AMR) AF: 0.984 AC: 15067 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3424 AN: 3472

East Asian (EAS) AF: 0.785 AC: 4072 AN: 5184

South Asian (SAS) AF: 0.982 AC: 4727 AN: 4814

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 68000 AN: 68042

Other (OTH) AF: 0.969 AC: 2046 AN: 2112

Alfa AF: 0.983 Hom.: 229832

Bravo AF: 0.955

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 0.998 AC: 3848

ESP6500AA AF: 0.895 AC: 3945

ESP6500EA AF: 0.999 AC: 8590

ExAC AF: 0.972 AC: 118061

Asia WGS AF: 0.907 AC: 3150 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.46
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.082
ClinPred		0.0018	T
GERP RS		4.7
Varity_R		0.034
gMVP		0.28
Mutation Taster		=19/181	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.13
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: rs1041135; hg19: chr10-15573050; COSMIC: COSV107482810;