chr17-44372412-G-T

Variant names:

• chr17-44372412-G-T
• NM_000419.5:c.3072C>A
• ITGA2B p.Phe1024Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_000419.5(ITGA2B):​c.3072C>A​(p.Phe1024Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1024I) has been classified as Likely pathogenic. The gene ITGA2B is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14
• Publications: 0 publications found

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ITGA2B Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for ITGA2B are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44372414-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2572659.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2307 (below the threshold of 3.09). Trascript score misZ: 1.3195 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, Glanzmann thrombasthenia 1, platelet-type bleeding disorder 16, Glanzmann thrombasthenia, Glanzmann's thrombasthenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. 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
	ITGA2B	NM_000419.5	MANE Select	c.3072C>A	p.Phe1024Leu	missense	Exon 30 of 30	NP_000410.2	P08514-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.3072C>A	p.Phe1024Leu	missense	Exon 30 of 30	ENSP00000262407.5	P08514-1
	ITGA2B	ENST00000901307.1		c.2958C>A	p.Phe986Leu	missense	Exon 29 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.2955C>A	p.Phe985Leu	missense	Exon 29 of 29	ENSP00000619736.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.96
gMVP		0.86

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-42449780;