rs572295823

chr7-80661109-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001001548.3(CD36):c.332_333del(p.Thr111SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,030 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: CD36 NM_001001548.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.883

Genes affected

CD36 (HGNC:1663): (CD36 molecule (CD36 blood group)) The protein encoded by this gene is the fourth major glycoprotein of the platelet surface and serves as a receptor for thrombospondin in platelets and various cell lines. Since thrombospondins are widely distributed proteins involved in a variety of adhesive processes, this protein may have important functions as a cell adhesion molecule. It binds to collagen, thrombospondin, anionic phospholipids and oxidized LDL. It directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and it binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport. Mutations in this gene cause platelet glycoprotein deficiency. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-80661109-AAC-A is Pathogenic according to our data. Variant chr7-80661109-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 225309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD36	NM_001001548.3	c.332_333del	p.Thr111SerfsTer22	frameshift_variant	5/15	ENST00000447544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD36	ENST00000447544.7	c.332_333del	p.Thr111SerfsTer22	frameshift_variant	5/15	5	NM_001001548.3	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00116 AC: 290 AN: 250890 Hom.: 4 AF XY: 0.00100 AC XY: 136 AN XY: 135574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000234 AC: 342 AN: 1461698 Hom.: 3 AF XY: 0.000213 AC XY: 155 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00804

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0130

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000461

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Platelet-type bleeding disorder 10 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2018	The CD36 c.332_333delCA (p.Thr111SerfsTer22) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr111SerfsTer22 variant has been reported in at least five studies in which it is found in at least twelve individuals with platelet glycoprotein IV deficiency, including in one in a homozygous state, in five in a compound heterozygous state, and in at least five in a heterozygous state, and in one additional individual with unknown zygosity (Kashiwagi et al. 1994; Yanai et al. 2000; Xu et al. 2013; Li et al. 2015; Masuda et al. 2015). In these studies, all the individuals are reported as generally healthy but failing to express CD36 on their platelets. The p.Thr111SerfsTer22 variant has been described as one of the most common variants associated with platelet glycoprotein IV deficiency in the Southern Chinese population (Xu et al. 2013). The variant was also found in a heterozygous state in three individuals with cerebral malaria (Omi et al. 2002). Control data are unavailable for this variant, which is reported at a frequency of 0.018849 in the East Asian population of the 1000 Genomes Project. Flow cytometry found four of the heterozygous patients were negative for CD36 expression and one heterozygote had a normal phenotype but had significantly reduced CD36 expression (Li et al. 2015; Masuda et al. 2015). Based on the collective evidence, the p.Thr111SerfsTer22 variant is classified as pathogenic for platelet glycoprotein IV deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 22, 2021	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001001547.2:c.332_333delCA in the CD36 gene has an allele frequency of 0.016 in East Asian subpopulation in the gnomAD database. The CD36 c.332_333delCA (p.Thr111SerfsTer22) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr111SerfsTer22 variant has been reported in individuals with platelet glycoprotein IV deficiency, including in one in a homozygous state, in five in a compound heterozygous state with 1228_1239del, Arg386Trp, Gln74Term (PMID: 23966019; 25330908; 25798958). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PP4; PM3_Strong. -
Pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Platelet-type bleeding disorder 10;C1970028:Malaria, susceptibility to;C1970441:Coronary heart disease, susceptibility to, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs572295823; hg19: chr7-80290425;