7-80671101-GAAAA-GAAAAA

Variant names:

• chr7-80671101-G-GA
• rs70961716
• NM_001001548.3:c.949dupA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_001001548.3(CD36):​c.949dupA​(p.Ile317AsnfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,352 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: CD36 NM_001001548.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.62
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-80671101-G-GA is Pathogenic according to our data. Variant chr7-80671101-G-GA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001548.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD36	NM_001001548.3	MANE Select	c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 15	NP_001001548.1
	CD36	NM_000072.3		c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 14	NP_000063.2
	CD36	NM_001001547.3		c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 14	NP_001001547.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD36	ENST00000447544.7	TSL:5 MANE Select	c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 15	ENSP00000415743.2
	CD36	ENST00000309881.11	TSL:1	c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 14	ENSP00000308165.7
	CD36	ENST00000394788.7	TSL:1	c.949dupA	p.Ile317AsnfsTer36	frameshift	Exon 10 of 14	ENSP00000378268.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 250744 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461148 Hom.: 2 Cov.: 29 AF XY: 0.000201 AC XY: 146 AN XY: 726918

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00566 AC: 224 AN: 39594

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111602

Other (OTH) AF: 0.000133 AC: 8 AN: 60360

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74406

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Platelet-type bleeding disorder 10 Pathogenic:4

Nov 21, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CD36 c.949dupA (p.Ile317AsnfsTer36) variant results in a frameshift and is predicted to result in premature termination of the protein. The variant has been reported in two studies in which it is found in four individuals affected with platelet glycoprotein IV deficiency. Hanawa et al. (2002) reported a family with an affected mother who was homozygous for p.Ile317AsnfsTer36 variant and two affected children who carried the variant in a compound heterozygous state with a pathogenic missense variant. Kashiwagi et al. (1996) reported an additional individual who carried the p.Ile317AsnfsTer36 variant in a compound heterozygote state with a second null allele. Control data are unavailable for this variant, which is reported at a frequency of 0.000816 in the East Asian population of the Exome Aggregation Consortium. Based on the potential impact of frameshift variants and evidence, the p.Ile317AsnfsTer36 variant is classified as likely pathogenic for platelet glycoprotein IV deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Allele frequency is greater than expected for disorder.

Mar 26, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs70961716; hg19: chr7-80300417; COSMIC: COSV59211416; COSMIC: COSV59211416;