chr17-47253892-T-C

Variant names:

• chr17-47253892-T-C
• rs1022839092
• NM_000212.3:c.31T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM3 PP4_Strong PM2_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The c.31T>C (p.Trp11Arg) missense variant has been reported in at least 3 probands (PMIDs: 25728920, 28748566, 25373348), at least one of whom (PMID:25728920) meets criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. Two homozygotes (PM3) and one compound heterozygote (with Likely Pathogenic Cys486Trp variant) has been observed. It is absent from controls in gnomADv2.1.1 (PM2_supporting. The expression of αIIbβ3 on the surface of HEK cells was evaluated by flow cytometry and showed no detectable αlIbβ3 protein (PMID:36122578; PS3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PS3, PM2_supporting, PM3, and PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291240306/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 0.891
• Publications: 3 publications found

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ITGB3 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann thrombasthenia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bleeding disorder, platelet-type, 24

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259753 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. 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
	ITGB3	NM_000212.3	MANE Select	c.31T>C	p.Trp11Arg	missense	Exon 1 of 15	NP_000203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.31T>C	p.Trp11Arg	missense	Exon 1 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.31T>C	p.Trp11Arg	missense	Exon 1 of 9	ENSP00000461626.1	I3L4X8
	ITGB3	ENST00000696963.1		c.31T>C	p.Trp11Arg	missense	Exon 1 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151742 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 0.0000376 AC: 44 AN: 1169378 Hom.: 0 Cov.: 30 AF XY: 0.0000370 AC XY: 21 AN XY: 568196

African (AFR) AF: 0.00 AC: 0 AN: 24312

American (AMR) AF: 0.00 AC: 0 AN: 16120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18612

East Asian (EAS) AF: 0.00 AC: 0 AN: 26816

South Asian (SAS) AF: 0.00 AC: 0 AN: 41552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3390

European-Non Finnish (NFE) AF: 0.0000456 AC: 44 AN: 964566

Other (OTH) AF: 0.00 AC: 0 AN: 46704

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151742 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74152

African (AFR) AF: 0.0000242 AC: 1 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15224

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glanzmann thrombasthenia (1)
1	-	-	Glanzmann thrombasthenia 2 (1)
1	-	-	Myocardial infarction, susceptibility to;C5543273:Glanzmann thrombasthenia 2;C5543280:Bleeding disorder, platelet-type, 24 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.89
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.97	N
Sift	Uncertain	0.011	D
Sift4G	Benign	0.28	T
Polyphen		0.44	B
Vest4		0.65
MutPred		0.70		Gain of disorder (P = 0)
MVP		0.90
MPC		0.90
ClinPred		0.23	T
GERP RS		2.3
PromoterAI		-0.050	Neutral
Varity_R		0.31
gMVP		0.81
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs1022839092; hg19: chr17-45331258;