rs75326924

Positions:

chr7-80656687-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP3PP5BP4BS1_SupportingBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.97

Variant links:

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]

CD36 links:

CD36 (HGNC:):

CD36 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=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 GnomAdExome4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD36	NM_001001548.3 linkuse as main transcript	c.268C>T	p.Pro90Ser	missense_variant	4/15	ENST00000447544.7	NP_001001548.1	P16671-1A4D1B1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD36	ENST00000447544.7 linkuse as main transcript	c.268C>T	p.Pro90Ser	missense_variant	4/15	5	NM_001001548.3	ENSP00000415743.2		P16671-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00100

AC XY:

136

AN XY:

135470

show subpopulations

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.:

Cov.:

AF XY:

0.000873

AC XY:

635

AN XY:

726996

show subpopulations

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:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74352

show subpopulations

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.:

Bravo

AF:

0.000125

ExAC

AF:

0.00135

AC:

164

Asia WGS

AF:

0.00578

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 10

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
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, 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. -

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

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

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

LIST_S2

Uncertain

0.97

.;.;D;D;.;D;D;D;D;.;.;D;D;D;D

MetaRNN

Benign

0.024

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.7

H;H;.;.;.;.;H;H;H;H;H;.;H;.;.

PrimateAI

Uncertain

0.50

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over