rs75326924

chr7-80656687-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP3 PP5 BP4 BS1_Supporting BS2

The NM_001001548.3(CD36):c.268C>T(p.Pro90Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000837 in 1,613,448 control chromosomes in the GnomAD database, including 38 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 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (38 hom.)
• Consequence: CD36 NM_001001548.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 6.97

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 Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 7-80656687-C-T is Pathogenic according to our data. Variant chr7-80656687-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13535.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr7-80656687-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.024205416).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000891 (1302/1461304) while in subpopulation EAS AF= 0.0325 (1288/39632). AF 95% confidence interval is 0.031. There are 38 homozygotes in gnomad4_exome. There are 635 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD36	NM_001001548.3	c.268C>T	p.Pro90Ser	missense_variant	4/15	ENST00000447544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD36	ENST00000447544.7	c.268C>T	p.Pro90Ser	missense_variant	4/15	5	NM_001001548.3	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00931

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: 0.00114 AC: 286 AN: 250710 Hom.: 10 AF XY: 0.00100 AC XY: 136 AN XY: 135470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000891 AC: 1302 AN: 1461304 Hom.: 38 Cov.: 31 AF XY: 0.000873 AC XY: 635 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0325

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00933

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000740 Hom.: 2

Bravo AF: 0.000125

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.00578 AC: 20 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Platelet-type bleeding disorder 10 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 26, 2016	Across a selection of the available literature, the CD36 c.268C>T (p.Pro90Ser) missense variant has been identified in at least 18 individuals with platelet glycoprotein IV deficiency, including in a homozygous state in at least 11 patients, in a compound heterozygous state in at least five patients, in one individual who was homozygous for the p.Pro90Ser variant and heterozygous for an insertion variant, and in one individual who carried the p.Pro90Ser variant, an insertion variant, and an additional missense variant (Kashiwagi H et al. 1993; Yanai H et al. 2000a; Hanawa et al. 2002). The p.Pro90Ser variant was reported in 0-3.5% of controls, but the allele frequencies were significantly higher in patients (24.5-28.6%) (Yanai et al. 2000a; Yanai et al. 2000b). The p.Pro90Ser variant is reported at a frequency of 0.04088 in the Japanese from Tokyo, Japan population of the 1000 Genomes Project. Functional studies showed that the p.Pro90Ser variant prevented maturation of the CD36 protein leading to degradation of the mutated precursor (Kashiwagi et al. 1995). The Pro90 residue is conserved in all members of the CD36 family. Based on the collective evidence, the p.Pro90Ser 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2019	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001001547.2:c.268C>T in the CD36 gene has an allele frequency of 0.014 in East Asian subpopulation in the gnomAD database. The c.268C>T (p.Pro90Ser) variant previously known as c.478C>T, has been reported in 5 homozygous, and 3 compound heterozygous individuals (two with 1159A insertion and one with 1447C) with type I CD36 deficiency (PMID: 11950861). In vitro functional provide support that this variant confers reduced expression in patient cell lines (PMID: 25798958; 7533783). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -

Inherited bleeding disorder, platelet-type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 09, 2020

The p.Pro90Ser variant in CD36, previously known as c.478C>T, has been reported in at least 17 homozygous, and 9 compound heterozygous individuals (predominantly individuals of Asian descent) with CD36 deficiency (type I or II, also known as platelet glycoprotein IV deficiency) (Kashiwagi 1995 PMID: 7533783, Yanai 2000a PMID: 11019968, Yanai 2000b PMID: 10946357, Kajihara 2001 PMID: 11718687, Hanawa 2002 PMID: 11950861, Hames 2014 PMID: 24917573, and Masuda 2015 PMID: 25798958). This variant also segregated with disease in 3 family members from 3 families (Yanai 2000a PMID: 11019968, Hanawa 2002 PMID: 11950861, Hames 2014 PMID: 24917573). In vitro functional provide support that this variant confers reduced expression in patient cell lines (Kashiwagi 1995 PMID: 7533783 and Masuda 2015 PMID: 25798958). This variant has also been reported in ClinVar (Variation ID 13535). This variant has been identified in 1.43% (284/19884) of East Asian chromosomes by gnomAD (http://gnomAD.broadinstitute.org). In summary, the p.Pro90Ser variant meets criteria to be classified as pathogenic for CD36 deficiency in an autosomal recessive manner based upon its occurrence in affected individuals and available functional studies. ACMG/AMP Criteria applied: PM3_Very Strong, PP1, PP3, PS3_Supporting. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 08, 2023

Variant summary: CD36 c.268C>T (p.Pro90Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250710 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 10 homozygotes. Due to the possibility of sub-clinical presentation and/or lack of phenotype information in this cohort, this frequency does not allow conclusions about variant significance. The c.268C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with features of type 1 CD36 deficiency (example, Kashiwagi_1995, Hames_2014, Masuda_2015, Hanawa_2002). Some of these studies also reported the variant as a heterozygous genotype in individuals with type II CD36 deficiency. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although one study has reported that this variant leads to CD36 deficiency via a defect in post-translational modification (Kashiwagi_1995). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 24917573, 7533783, 25798958, 11019968, 11950861). All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;D;.;T;T;T;.;.;.;D;D;.;D;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.024	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.;.;H;H;H;H;H;.;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;D;D;.;D;.;.
Vest4		0.98
MVP		0.94
MPC		0.00037
ClinPred		0.29	T
GERP RS		5.5
Varity_R		0.97
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs75326924; hg19: chr7-80286003; COSMIC: COSV59213512; COSMIC: COSV59213512;