10-15519382-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting
The NM_003638.3(ITGA8):c.3013A>G(p.Asn1005Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
ITGA8
NM_003638.3 missense
NM_003638.3 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 4.86
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
?
In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ITA8_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.09442288).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000657 (10/152182) while in subpopulation AFR AF= 0.000241 (10/41452). AF 95% confidence interval is 0.00013. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA8 | NM_003638.3 | c.3013A>G | p.Asn1005Asp | missense_variant | 29/30 | ENST00000378076.4 | |
ITGA8 | NM_001291494.2 | c.2968A>G | p.Asn990Asp | missense_variant | 28/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA8 | ENST00000378076.4 | c.3013A>G | p.Asn1005Asp | missense_variant | 29/30 | 1 | NM_003638.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251148Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135724
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461440Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727042
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2023 | The c.3013A>G (p.N1005D) alteration is located in exon 29 (coding exon 29) of the ITGA8 gene. This alteration results from a A to G substitution at nucleotide position 3013, causing the asparagine (N) at amino acid position 1005 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at