chr17-47253881-C-T

Variant names:

• chr17-47253881-C-T
• rs1216806597
• NM_000212.3:c.20C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000212.3(ITGB3):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.374
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1647791).

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.20C>T	p.Pro7Leu	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.20C>T	p.Pro7Leu	missense	Exon 1 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.20C>T	p.Pro7Leu	missense	Exon 1 of 9	ENSP00000461626.1	I3L4X8
	ITGB3	ENST00000696963.1		c.20C>T	p.Pro7Leu	missense	Exon 1 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1120918 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 538972

African (AFR) AF: 0.00 AC: 0 AN: 23198

American (AMR) AF: 0.00 AC: 0 AN: 11016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16232

East Asian (EAS) AF: 0.00 AC: 0 AN: 26298

South Asian (SAS) AF: 0.00 AC: 0 AN: 30618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 941172

Other (OTH) AF: 0.00 AC: 0 AN: 44742

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74086

African (AFR) AF: 0.00 AC: 0 AN: 41350

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67868

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	8.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.37
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.88	N
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.075	T
Polyphen		0.030	B
Vest4		0.18
MutPred		0.44		Loss of glycosylation at P7 (P = 0.0026)
MVP		0.89
MPC		0.42
ClinPred		0.17	T
GERP RS		2.1
PromoterAI		-0.14	Neutral
Varity_R		0.053
gMVP		0.64

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: rs1216806597; hg19: chr17-45331247;