rs121918037

chr3-129061951-T-Cchr3-129061951-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000174.5(GP9):c.212T>C(p.Phe71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,770 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F71C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GP9 NM_000174.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a turn (size 5) in uniprot entity GPIX_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000174.5
• 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-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1491487.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 3-129061951-T-C is Pathogenic according to our data. Variant chr3-129061951-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129061951-T-C is described in Lovd as [Pathogenic]. Variant chr3-129061951-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP9	NM_000174.5	c.212T>C	p.Phe71Ser	missense_variant	3/3	ENST00000307395.5
GP9	XM_047447997.1	c.212T>C	p.Phe71Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP9	ENST00000307395.5	c.212T>C	p.Phe71Ser	missense_variant	3/3	1	NM_000174.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461534 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard Soulier syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2022	Variant summary: GP9 c.212T>C (p.Phe71Ser) results in a non-conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248306 control chromosomes (gnomAD). c.212T>C has been reported in the literature in multiple homozygous individuals affected with Bernard Soulier Syndrome (Noris_1997, Suzuki_1997, Sumitha_2011, Sanchez-Guiu_2014, Savoia_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however it is suggested that disruption of the the leucine-rich repeat motif impairs surface expression of the GPIb/IX/V complex (Sumitha_2011, Suzuki_1997). Other substitutions at this codon (Phe>Cys) have also been found to impact surface GPIb/IX/V expression (Sumitha_2011). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and the other as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Bernard-Soulier syndrome type C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 71 of the GP9 protein (p.Phe71Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Bernard-Soulier Syndrome and/or Bernard-Soulier syndrome (PMID: 9163595, 21699652, 25539746, 28395735, 29636940). This variant is also known as Phe55Ser. ClinVar contains an entry for this variant (Variation ID: 13531). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Macrothrombocytopenia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	0.87	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.96
MPC		0.93
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.80
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918037; hg19: chr3-128780794;