chr17-47253862-A-T

Variant names:

• chr17-47253862-A-T
• rs2064976742
• NM_000212.3:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000212.3(ITGB3):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: ITGB3 NM_000212.3 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.875
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 48 codons. Genomic position: 47274481. Lost 0.060 part of the original CDS.
• 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.1A>T	p.Met1?	initiator_codon	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.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000461626.1	I3L4X8
	ITGB3	ENST00000696963.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082630 Hom.: 0 Cov.: 30 AF XY: 0.00000194 AC XY: 1 AN XY: 515814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22358

American (AMR) AF: 0.00 AC: 0 AN: 8276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13868

East Asian (EAS) AF: 0.00 AC: 0 AN: 25484

South Asian (SAS) AF: 0.00 AC: 0 AN: 22810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2934

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 921784

Other (OTH) AF: 0.00 AC: 0 AN: 43004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.90	T
PhyloP100		0.88
PROVEAN	Benign	-0.33	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.81
MutPred		1.0		Gain of methylation at R6 (P = 0.1535)
MVP		0.94
ClinPred		1.0	D
GERP RS		3.3
PromoterAI		0.19	Neutral
Varity_R		0.95
gMVP		0.72

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: rs2064976742; hg19: chr17-45331228;