17-44372414-A-T

Position:

• chr17-44372414-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000419.5(ITGA2B):​c.3070T>A​(p.Phe1024Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Integrin alpha-IIb light chain, form 1 (size 148) in uniprot entity ITA2B_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000419.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3070T>A	p.Phe1024Ile	missense_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3121T>A	p.Phe1041Ile	missense_variant	29/29
ITGA2B	XM_011524750.2	c.3106T>A	p.Phe1036Ile	missense_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3070T>A	p.Phe1024Ile	missense_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.2386T>A	p.Phe796Ile	missense_variant	25/25
ITGA2B	ENST00000587295.5	c.265T>A	p.Phe89Ile	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Platelet-type bleeding disorder 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.89		Gain of MoRF binding (P = 0.1001);
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42449782;