rs41361752

chr17-44380309-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000419.5(ITGA2B):c.1545-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,230 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: ITGA2B NM_000419.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003231
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.611

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-44380309-G-T is Benign according to our data. Variant chr17-44380309-G-T is described in ClinVar as [Benign]. Clinvar id is 235314.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1983/152354) while in subpopulation AFR AF= 0.045 (1873/41576). AF 95% confidence interval is 0.0434. There are 45 homozygotes in gnomad4. There are 931 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.1545-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262407.6
ITGA2B	XM_011524749.2	c.1698-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ITGA2B	XM_011524750.2	c.1698-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1545-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.976-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ITGA2B	ENST00000592226.5	n.1018-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5
ITGA2B	ENST00000592462.5	n.340-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1980 AN: 152236 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00357 AC: 898 AN: 251470 Hom.: 21 AF XY: 0.00263 AC XY: 357 AN XY: 135910

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00144 AC: 2109 AN: 1461876 Hom.: 50 Cov.: 33 AF XY: 0.00125 AC XY: 911 AN XY: 727238

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.0130 AC: 1983 AN: 152354 Hom.: 45 Cov.: 32 AF XY: 0.0125 AC XY: 931 AN XY: 74510

Gnomad4 AFR AF: 0.0450

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00652 Hom.: 4

Bravo AF: 0.0147

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Sep 07, 2023	After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.1545-8C>A, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.04631 (1156/24960 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets benign criterion (BA1). In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.57 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 and BP7 (PD VCEP specifications version 2.1). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.9
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.15
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

Publications

LitVar

Other links and lift over

dbSNP: rs41361752; hg19: chr17-42457677;