rs76066357

Variant names:

• chr17-44385686-G-C
• rs76066357
• NM_000419.5:c.439C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.439C>G variant in ITGA2B is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 147 (p.Leu147Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01420 (1822/128308 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.053, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant is also classified as Benign/Likely benign in ClinVar and was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. 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 PDVCEP: BA1 and BP4 (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA351291/MONDO:0100326/011

• Frequency:
  • Genomes: 𝑓 0.0092 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (135 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.0980
• Publications: 12 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: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.439C>G	p.Leu147Val	missense	Exon 4 of 30	NP_000410.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.439C>G	p.Leu147Val	missense	Exon 4 of 30	ENSP00000262407.5
	ITGA2B	ENST00000592944.1	TSL:5	n.124C>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1403 AN: 152248 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00915 AC: 2280 AN: 249236 AF XY: 0.00916

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.00622

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00755

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0116 AC: 17008 AN: 1461340 Hom.: 135 Cov.: 35 AF XY: 0.0116 AC XY: 8424 AN XY: 727004

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.00644 AC: 288 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 330 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00289 AC: 249 AN: 86254

European-Finnish (FIN) AF: 0.00697 AC: 369 AN: 52928

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5766

European-Non Finnish (NFE) AF: 0.0136 AC: 15093 AN: 1111978

Other (OTH) AF: 0.00911 AC: 550 AN: 60382

GnomAD4 genome AF: 0.00920 AC: 1402 AN: 152366 Hom.: 9 Cov.: 33 AF XY: 0.00871 AC XY: 649 AN XY: 74504

African (AFR) AF: 0.00233 AC: 97 AN: 41590

American (AMR) AF: 0.00869 AC: 133 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1026 AN: 68036

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0126 Hom.: 16

Bravo AF: 0.00867

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.00928 AC: 1127

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0153

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Glanzmann thrombasthenia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.098
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.053
Sift	Benign	0.12	T
Sift4G	Benign	0.29	T
Polyphen		0.15	B
Vest4		0.22
MVP		0.60
MPC		1.2
ClinPred		0.0028	T
GERP RS		3.5
PromoterAI		-0.060	Neutral
Varity_R		0.15
gMVP		0.63
Mutation Taster		=79/21	polymorphism

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: rs76066357; hg19: chr17-42463054; COSMIC: COSV99289415; COSMIC: COSV99289415;