chr17-44376323-T-A

Variant names:

• chr17-44376323-T-A
• rs74475415
• NM_000419.5:c.2333A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000419.5(ITGA2B):​c.2333A>T​(p.Gln778Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. Q778P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Glanzmann thrombasthenia

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

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44376323-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225393.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 Glanzmann's thrombasthenia, autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 16, Glanzmann thrombasthenia 1, Glanzmann thrombasthenia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2155332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.2333A>T	p.Gln778Leu	missense_variant	Exon 23 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2486A>T	p.Gln829Leu	missense_variant	Exon 23 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.2486A>T	p.Gln829Leu	missense_variant	Exon 23 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2333A>T	p.Gln778Leu	missense_variant	Exon 23 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1763A>T	p.Gln588Leu	missense_variant	Exon 19 of 25			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.1128A>T		non_coding_transcript_exon_variant	Exon 12 of 15	5
ITGA2B	ENST00000587295.5	c.-140A>T		upstream_gene_variant		3		ENSP00000467269.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.17
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.055
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.61		Loss of disorder (P = 0.0351);
MVP		0.53
MPC		0.28
ClinPred		0.082	T
GERP RS		-3.0
PromoterAI		-0.21	Neutral
Varity_R		0.15
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74475415; hg19: chr17-42453691;