NM_000174.5:c.181_182delAAinsTC

Variant names:

• chr3-129061920-AA-TC
• NM_000174.5:c.181_182delAAinsTC
• GP9 p.Asn61Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Very_Strong PP2

The NM_000174.5(GP9):​c.181_182delAAinsTC​(p.Asn61Ser) variant causes a missense change. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N61K) has been classified as Uncertain significance. 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: Not reported in ClinVar
• Conservation: PhyloP100: 5.70
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000174.5 (GP9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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.

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.181_182delAAinsTC	p.Asn61Ser	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.181_182delAAinsTC	p.Asn61Ser	missense	N/A	ENSP00000303942.4	P14770
	GP9	ENST00000900754.1		c.181_182delAAinsTC	p.Asn61Ser	missense	N/A	ENSP00000570813.1
	GP9	ENST00000900755.1		c.181_182delAAinsTC	p.Asn61Ser	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-128780763;