chr10-15519316-C-T

Variant names:

• chr10-15519316-C-T
• rs150922478
• NM_003638.3:c.3079G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003638.3(ITGA8):​c.3079G>A​(p.Ala1027Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000463 in 1,613,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: ITGA8 NM_003638.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.88
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029220253).
• BP6: Variant 10-15519316-C-T is Benign according to our data. Variant chr10-15519316-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2065706.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000533 (81/152072) while in subpopulation NFE AF = 0.000794 (54/68020). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.3079G>A	p.Ala1027Thr	missense	Exon 29 of 30	NP_003629.2	P53708
	ITGA8	NM_001291494.2		c.3034G>A	p.Ala1012Thr	missense	Exon 28 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.3079G>A	p.Ala1027Thr	missense	Exon 29 of 30	ENSP00000367316.3	P53708
	ITGA8	ENST00000882526.1		c.2977G>A	p.Ala993Thr	missense	Exon 28 of 29	ENSP00000552585.1
	ITGA8	ENST00000967017.1		c.2932G>A	p.Ala978Thr	missense	Exon 27 of 28	ENSP00000637076.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000669 AC: 168 AN: 251100 AF XY: 0.000604

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00306

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000456 AC: 666 AN: 1461388 Hom.: 1 Cov.: 31 AF XY: 0.000435 AC XY: 316 AN XY: 726982

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000336 AC: 15 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00345 AC: 184 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000384 AC: 427 AN: 1111806

Other (OTH) AF: 0.000398 AC: 24 AN: 60374

GnomAD4 genome AF: 0.000533 AC: 81 AN: 152072 Hom.: 0 Cov.: 33 AF XY: 0.000485 AC XY: 36 AN XY: 74272

African (AFR) AF: 0.0000725 AC: 3 AN: 41386

American (AMR) AF: 0.000393 AC: 6 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68020

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.094
Sift	Uncertain	0.017	D
Sift4G	Benign	0.14	T
Polyphen		0.10	B
Vest4		0.38
MVP		0.72
MPC		0.093
ClinPred		0.076	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.55
Mutation Taster		=44/56	disease causing

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: rs150922478; hg19: chr10-15561315; COSMIC: COSV65231949;