17-4933915-A-G

Variant names:

• chr17-4933915-A-G
• rs2586529
• NM_000173.7:c.1311A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000173.7(GP1BA):c.1311A>G (p.Pro437=) synonymous variant occurs at a Grpmax filtering allele frequency of 0.8560 (based 186885/217504 alleles in the European non-Finnish population) in gnomADv4.1, which is higher than the ClinGen PD VCEP threshold (>0.001) for BA1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing (delta score 0.00) and a PhyloP score of 0.011 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8314972/MONDO:0009276/079

• Frequency:
  • Genomes: 𝑓 0.62 (2756 hom., cov: 0)
  • Exomes 𝑓: 0.83 (99379 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP1BA NM_000173.7 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.124
• Publications: 9 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1311A>G	p.Pro437Pro	synonymous	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.1311A>G	p.Pro437Pro	synonymous	Exon 2 of 2	ENSP00000329380.5
	CHRNE	ENST00000649830.1		c.-888+427T>C		intron	N/A	ENSP00000496907.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 7187 AN: 11514 Hom.: 2746 Cov.: 0

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.369 AC: 37152 AN: 100604 AF XY: 0.389

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.0860

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.325

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.828 AC: 242500 AN: 292884 Hom.: 99379 Cov.: 0 AF XY: 0.824 AC XY: 120707 AN XY: 146426

African (AFR) AF: 0.744 AC: 8037 AN: 10798

American (AMR) AF: 0.784 AC: 11817 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 6251 AN: 8212

East Asian (EAS) AF: 0.455 AC: 2194 AN: 4826

South Asian (SAS) AF: 0.752 AC: 12845 AN: 17092

European-Finnish (FIN) AF: 0.670 AC: 6596 AN: 9852

Middle Eastern (MID) AF: 0.762 AC: 916 AN: 1202

European-Non Finnish (NFE) AF: 0.864 AC: 184547 AN: 213550

Other (OTH) AF: 0.757 AC: 9297 AN: 12286

GnomAD4 genome AF: 0.625 AC: 7211 AN: 11544 Hom.: 2756 Cov.: 0 AF XY: 0.611 AC XY: 3355 AN XY: 5494

African (AFR) AF: 0.777 AC: 3408 AN: 4388

American (AMR) AF: 0.606 AC: 679 AN: 1120

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 183 AN: 298

East Asian (EAS) AF: 0.251 AC: 141 AN: 562

South Asian (SAS) AF: 0.326 AC: 114 AN: 350

European-Finnish (FIN) AF: 0.325 AC: 207 AN: 636

Middle Eastern (MID) AF: 0.656 AC: 21 AN: 32

European-Non Finnish (NFE) AF: 0.591 AC: 2338 AN: 3954

Other (OTH) AF: 0.575 AC: 92 AN: 160

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bernard Soulier syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.20
PhyloP100		-0.12
Mutation Taster		=19/81	disease causing (long InDel)

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: rs2586529; hg19: chr17-4837210; COSMIC: COSV56698557; COSMIC: COSV56698557;