3-129061951-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000174.5(GP9):c.212T>G(p.Phe71Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,534 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F71S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.70

Publications

10 publications found

Variant links:

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), Orphanet, ClinGen

GP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-129061951-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 3-129061951-T-G is Pathogenic according to our data. Variant chr3-129061951-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1491487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5 link	c.212T>G	p.Phe71Cys	missense_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1 link	c.212T>G	p.Phe71Cys	missense_variant	Exon 2 of 2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5 link	c.212T>G	p.Phe71Cys	missense_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248306

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727106

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000145

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 08, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28960434, 21699652, 24934643, 9163595, 25539746, 29636940)

May 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces phenylalanine with cysteine at codon 71 of the GP9 protein (p.Phe71Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs121918037, ExAC 0.002%). This variant has been observed in individual(s) with Bernard-Soulier syndrome (PMID: 21699652). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Phe71 amino acid residue in GP9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21699652, 9163595, 29636940, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Bernard Soulier syndrome

Pathogenic:1

May 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GP9 c.212T>G (p.Phe71Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 248306 control chromosomes. c.212T>G has been observed in individual(s) affected with Bernard Soulier Syndrome (Sumitha_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.212T>C, p.Phe71Ser), supporting the critical relevance of codon 71 to GP9 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 21699652). ClinVar contains an entry for this variant (Variation ID: 1491487). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.9

PhyloP100

3.7

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.69

ClinPred

1.0

GERP RS

4.2

Varity_R

0.69

gMVP

0.87

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over