chr17-47253896-C-A

Variant names:

• chr17-47253896-C-A
• rs1051430
• NM_000212.3:c.35C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000212.3(ITGB3):​c.35C>A​(p.Ala12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,192,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.630
• Publications: 0 publications found

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ITGB3 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann thrombasthenia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bleeding disorder, platelet-type, 24

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259753 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. 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
	ITGB3	NM_000212.3	MANE Select	c.35C>A	p.Ala12Glu	missense	Exon 1 of 15	NP_000203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.35C>A	p.Ala12Glu	missense	Exon 1 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.35C>A	p.Ala12Glu	missense	Exon 1 of 9	ENSP00000461626.1	I3L4X8
	ITGB3	ENST00000696963.1		c.35C>A	p.Ala12Glu	missense	Exon 1 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1192242 Hom.: 0 Cov.: 30 AF XY: 0.00000344 AC XY: 2 AN XY: 581804

African (AFR) AF: 0.00 AC: 0 AN: 24904

American (AMR) AF: 0.00 AC: 0 AN: 18900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19460

East Asian (EAS) AF: 0.00 AC: 0 AN: 27084

South Asian (SAS) AF: 0.00 AC: 0 AN: 46984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3478

European-Non Finnish (NFE) AF: 0.00000205 AC: 2 AN: 975226

Other (OTH) AF: 0.00 AC: 0 AN: 47686

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.63
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N
Sift	Benign	0.15	T
Sift4G	Benign	0.75	T
Polyphen		0.078	B
Vest4		0.52
MutPred		0.55		Loss of MoRF binding (P = 0.0453)
MVP		0.93
MPC		0.49
ClinPred		0.11	T
GERP RS		2.1
PromoterAI		-0.059	Neutral
Varity_R		0.18
gMVP		0.82
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs1051430; hg19: chr17-45331262;