chr3-129061809-TGTAC-GTGGG

Variant names:

• chr3-129061809-TGTAC-GTGGG
• NM_000174.5:c.70_74delTGTACinsGTGGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP5_Moderate

The NM_000174.5(GP9):​c.70_74delTGTACinsGTGGG​(p.CysThr24ValGly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C24C) has been classified as Likely benign. The gene GP9 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GP9 NM_000174.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.46
• Publications: 0 publications found

Genes affected

GP9 (HGNC:4444): (glycoprotein IX platelet) This gene encodes a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib, a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor. The complete receptor complex includes noncovalent association of the alpha and beta subunits with the protein encoded by this gene and platelet glycoprotein V. Defects in this gene are a cause of Bernard-Soulier syndrome, also known as giant platelet disease. These patients have unusually large platelets and have a clinical bleeding tendency. [provided by RefSeq, Oct 2008]

GP9 Gene-Disease associations (from GenCC):

• Bernard-Soulier syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for GP9 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a domain LRRNT (size 34) in uniprot entity GPIX_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000174.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.1625 (below the threshold of 3.09). Trascript score misZ: 0.037799 (below the threshold of 3.09). GenCC associations: The gene is linked to Bernard-Soulier syndrome.
• PP5: Variant 3-129061809-TGTAC-GTGGG is Pathogenic according to our data. Variant chr3-129061809-TGTAC-GTGGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3588369.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000174.5. 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
	GP9	NM_000174.5	MANE Select	c.70_74delTGTACinsGTGGG	p.CysThr24ValGly	missense	N/A	NP_000165.1	P14770

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP9	ENST00000307395.5	TSL:1 MANE Select	c.70_74delTGTACinsGTGGG	p.CysThr24ValGly	missense	N/A	ENSP00000303942.4	P14770
	GP9	ENST00000900754.1		c.70_74delTGTACinsGTGGG	p.CysThr24ValGly	missense	N/A	ENSP00000570813.1
	GP9	ENST00000900755.1		c.70_74delTGTACinsGTGGG	p.CysThr24ValGly	missense	N/A	ENSP00000570814.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Bernard Soulier syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr3-128780652;