rs139921368

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.1232C>T	p.Pro411Leu	missense_variant	Exon 2 of 2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.1232C>T	p.Pro411Leu	missense_variant	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+506G>A		intron_variant	Intron 1 of 10			ENSP00000496907.1

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

GnomAD3 exomes AF: 0.000941 AC: 226 AN: 240218 Hom.: 0 AF XY: 0.00115 AC XY: 150 AN XY: 130852

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 SAS exome AF: 0.00370

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

Gnomad4 AFR exome AF: 0.0000322

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00621

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00543

Gnomad4 FIN exome AF: 0.0000922

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.00118

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000422

Gnomad4 ASJ AF: 0.00877

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00431

Gnomad4 FIN AF: 0.000110

Gnomad4 NFE AF: 0.000452

Gnomad4 OTH AF: 0.000508

Alfa AF: 0.000696 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.000997 AC: 120

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:1

Sep 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Bernard Soulier syndrome Benign:1

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

GP1BA-related disorder Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.88	D;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0080	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs139921368; hg19: chr17-4837131;