17-4932810-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000173.7(GP1BA):c.206C>T(p.Pro69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,024 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:2
• Conservation: PhyloP100: -1.39

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015892774).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (260/152328) while in subpopulation NFE AF= 0.00301 (205/68026). AF 95% confidence interval is 0.00268. There are 2 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.206C>T	p.Pro69Leu	missense_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.206C>T	p.Pro69Leu	missense_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+1532G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00175 AC: 435 AN: 249278 Hom.: 0 AF XY: 0.00169 AC XY: 229 AN XY: 135228

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.00248 AC: 3626 AN: 1461696 Hom.: 7 Cov.: 37 AF XY: 0.00246 AC XY: 1788 AN XY: 727132

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00300

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74476

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00157

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00327 AC: 28

ExAC AF: 0.00186 AC: 226

EpiCase AF: 0.00267

EpiControl AF: 0.00261

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2 Benign:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2021	DNA sequence analysis of the GP1BA gene demonstrated a sequence change, c.206C>T, in exon 2 that results in an amino acid change, p.Pro69Leu. This sequence change does not appear to have been previously described in individuals with GP1BA-related disorders. This sequence change has been described in the gnomAD database with a low frequency of 0.30% in the non-Finnish European subpopulation (dbSNP rs138825640). The p.Pro69Leu change affects a poorly conserved amino acid residue of the GP1BA protein. The p.Pro69Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of sufficient evidence, the clinical significance of the p.Pro69Leu change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2022	Variant summary: GP1BA c.206C>T (p.Pro69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 249278 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. c.206C>T has been reported in the literature in a family with macrothrombocytopenia and Bernard-Soulier syndrome. Both of these publications provided evidence supporting benign effect of this variant (example: Ghevaert_2008 and Bragadottir_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Bernard-Soulier syndrome, type A2, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Bernard Soulier syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.77
Dann	Benign	0.86
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.030
Sift	Uncertain	0.018	D;.
Sift4G	Benign	0.63	T;T
Vest4		0.19
MVP		0.40
MPC		0.53
ClinPred		0.011	T
GERP RS		-9.1
Varity_R		0.21
gMVP		0.65

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: rs138825640; hg19: chr17-4836105;