chr10-15531206-T-A

Variant names:

• chr10-15531206-T-A
• rs9333240
• NM_003638.3:c.2881-55A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003638.3(ITGA8):​c.2881-55A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 746,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: ITGA8 NM_003638.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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.2881-55A>T		intron	N/A	NP_003629.2	P53708
	ITGA8	NM_001291494.2		c.2836-55A>T		intron	N/A	NP_001278423.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA8	ENST00000378076.4	TSL:1 MANE Select	c.2881-55A>T		intron	N/A	ENSP00000367316.3	P53708
	ITGA8	ENST00000882526.1		c.2881-11794A>T		intron	N/A	ENSP00000552585.1
	ITGA8	ENST00000967017.1		c.2836-11794A>T		intron	N/A	ENSP00000637076.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000134 AC: 1 AN: 746764 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 378254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14858

American (AMR) AF: 0.00 AC: 0 AN: 15760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16180

East Asian (EAS) AF: 0.00 AC: 0 AN: 25802

South Asian (SAS) AF: 0.00 AC: 0 AN: 33814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2982

European-Non Finnish (NFE) AF: 0.00000178 AC: 1 AN: 561762

Other (OTH) AF: 0.00 AC: 0 AN: 33676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.79
PhyloP100		-0.54

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: rs9333240; hg19: chr10-15573205;