17-4932696-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_000173.7(GP1BA):c.92T>C(p.Val31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,613,460 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V31E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (6 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.219

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a domain LRRNT (size 30) in uniprot entity GP1BA_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000173.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.016739875).
• BS2: High Homozygotes in GnomAdExome at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.92T>C	p.Val31Ala	missense_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.92T>C	p.Val31Ala	missense_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+1646A>G		intron_variant

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

GnomAD3 exomes AF: 0.00125 AC: 312 AN: 249288 Hom.: 2 AF XY: 0.00129 AC XY: 174 AN XY: 135228

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 SAS exome AF: 0.000261

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

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.00128

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

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000589

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.00158 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

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Bernard Soulier syndrome;C1280798:Pseudo von Willebrand disease;C3277076:Bernard-Soulier syndrome, type A2, autosomal dominant Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.46	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.16
MVP		0.95
MPC		0.57
ClinPred		0.056	T
GERP RS		3.3
Varity_R		0.61
gMVP		0.54

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: rs201827537; hg19: chr17-4835991;