rs139921368

Variant names:

• chr17-4933836-C-T
• rs139921368
• NM_000173.7:c.1232C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000173.7(GP1BA):c.1232C>T variant in GP1BA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 411 (p.Pro411Leu). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.007836 (based on 54/5424) in the Middle Eastern population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets BA1. The computational predictor REVEL gives a score of 0.223, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). 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 and BP4 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8314930/MONDO:0009276/079

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 0.328
• Publications: 5 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
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, 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: Benign. The variant received -9 ACMG points.

• BP4: 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.1232C>T	p.Pro411Leu	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.1232C>T	p.Pro411Leu	missense	Exon 2 of 2	ENSP00000329380.5	P07359
	CHRNE	ENST00000649830.1		c.-888+506G>A		intron	N/A	ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes AF: 0.000589 AC: 83 AN: 140800 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000423

Gnomad ASJ AF: 0.00877

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00431

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.000452

Gnomad OTH AF: 0.000513

GnomAD2 exomes AF: 0.000941 AC: 226 AN: 240218 AF XY: 0.00115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.00555

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000952

Gnomad NFE exome AF: 0.000410

Gnomad OTH exome AF: 0.000846

GnomAD4 exome AF: 0.000729 AC: 969 AN: 1329802 Hom.: 3 Cov.: 38 AF XY: 0.000909 AC XY: 596 AN XY: 655794

African (AFR) AF: 0.0000322 AC: 1 AN: 31072

American (AMR) AF: 0.000380 AC: 15 AN: 39424

Ashkenazi Jewish (ASJ) AF: 0.00621 AC: 135 AN: 21736

East Asian (EAS) AF: 0.00 AC: 0 AN: 20284

South Asian (SAS) AF: 0.00543 AC: 369 AN: 67950

European-Finnish (FIN) AF: 0.0000922 AC: 4 AN: 43382

Middle Eastern (MID) AF: 0.0103 AC: 53 AN: 5158

European-Non Finnish (NFE) AF: 0.000314 AC: 329 AN: 1047252

Other (OTH) AF: 0.00118 AC: 63 AN: 53544

GnomAD4 genome AF: 0.000589 AC: 83 AN: 140918 Hom.: 0 Cov.: 26 AF XY: 0.000497 AC XY: 34 AN XY: 68438

African (AFR) AF: 0.00 AC: 0 AN: 38950

American (AMR) AF: 0.000422 AC: 6 AN: 14206

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 27 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 4106

South Asian (SAS) AF: 0.00431 AC: 18 AN: 4180

European-Finnish (FIN) AF: 0.000110 AC: 1 AN: 9068

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.000452 AC: 29 AN: 64216

Other (OTH) AF: 0.000508 AC: 1 AN: 1968

Alfa AF: 0.000715 Hom.: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.000997 AC: 120

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Bernard Soulier syndrome (1)
-	-	1	GP1BA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.0
DANN	Benign	0.88
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.33
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Vest4		0.079
MVP		0.86
MPC		0.11
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.080
gMVP		0.13
Mutation Taster		=90/10	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: rs139921368; hg19: chr17-4837131;