17-4932696-T-C

Variant names:

• chr17-4932696-T-C
• rs201827537
• NM_000173.7:c.92T>C

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000173.7(GP1BA):c.92T>C (p.Val31Ala) has been reported in one macrothrombocytopenia patient heterozygous for this variant (PMID:34400424) however the same variant was detected in the mother with normal laboratory parameters. No BSS patients have been reported to our knowledge. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0006253 (based on 784/1179792 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005; BS1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS1 (ClinGen Platelet Disorders VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8314693/MONDO:0009276/079

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (6 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 O:1
• Conservation: PhyloP100: 0.219
• Publications: 7 publications found

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]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000173.7. 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
	GP1BA	NM_000173.7	MANE Select	c.92T>C	p.Val31Ala	missense	Exon 2 of 2	NP_000164.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BA	ENST00000329125.6	TSL:1 MANE Select	c.92T>C	p.Val31Ala	missense	Exon 2 of 2	ENSP00000329380.5	P07359
	CHRNE	ENST00000649830.1		c.-888+1646A>G		intron	N/A	ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes AF: 0.000738 AC: 112 AN: 151762 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00125 AC: 312 AN: 249288 AF XY: 0.00129

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000991

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000874 AC: 1278 AN: 1461698 Hom.: 6 Cov.: 37 AF XY: 0.000893 AC XY: 649 AN XY: 727136

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53402

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000669 AC: 744 AN: 1111862

Other (OTH) AF: 0.00128 AC: 77 AN: 60372

GnomAD4 genome AF: 0.000738 AC: 112 AN: 151762 Hom.: 1 Cov.: 32 AF XY: 0.000540 AC XY: 40 AN XY: 74122

African (AFR) AF: 0.0000727 AC: 3 AN: 41258

American (AMR) AF: 0.000197 AC: 3 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67930

Other (OTH) AF: 0.00192 AC: 4 AN: 2078

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.000801

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000937 AC: 8

ExAC AF: 0.00111 AC: 134

EpiCase AF: 0.00169

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Bernard Soulier syndrome (1)
-	1	-	not provided (1)
-	-	-	Bernard Soulier syndrome;C1280798:Pseudo von Willebrand disease;C3277076:Bernard-Soulier syndrome, type A2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.017	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.22
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.16
MVP		0.95
MPC		0.57
ClinPred		0.056	T
GERP RS		3.3
PromoterAI		-0.0092	Neutral
Varity_R		0.61
gMVP		0.54
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201827537; hg19: chr17-4835991;