17-4933909-C-T

Variant names:

• chr17-4933909-C-T
• rs761456793
• NM_000173.7:c.1305C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000173.7(GP1BA):​c.1305C>T​(p.Thr435Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene GP1BA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (28 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP1BA NM_000173.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.466
• 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

Specifications for GP1BA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-4933909-C-T is Benign according to our data. Variant chr17-4933909-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 255465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.

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.1305C>T	p.Thr435Thr	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.1305C>T	p.Thr435Thr	synonymous	Exon 2 of 2	ENSP00000329380.5	P07359
	CHRNE	ENST00000649830.1		c.-888+433G>A		intron	N/A	ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 27 AN: 22248 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00149

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00180

Gnomad SAS AF: 0.00323

Gnomad FIN AF: 0.000623

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00272 AC: 350 AN: 128696 AF XY: 0.00307

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00149

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.000760

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00137 AC: 749 AN: 544916 Hom.: 28 Cov.: 7 AF XY: 0.00156 AC XY: 405 AN XY: 260258

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000410 AC: 6 AN: 14638

American (AMR) AF: 0.00573 AC: 75 AN: 13088

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 21 AN: 8980

East Asian (EAS) AF: 0.000848 AC: 3 AN: 3536

South Asian (SAS) AF: 0.0101 AC: 178 AN: 17660

European-Finnish (FIN) AF: 0.00199 AC: 16 AN: 8052

Middle Eastern (MID) AF: 0.000633 AC: 1 AN: 1580

European-Non Finnish (NFE) AF: 0.000938 AC: 431 AN: 459400

Other (OTH) AF: 0.00100 AC: 18 AN: 17982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00117 AC: 26 AN: 22274 Hom.: 0 Cov.: 0 AF XY: 0.000988 AC XY: 11 AN XY: 11130

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000559 AC: 5 AN: 8940

American (AMR) AF: 0.00149 AC: 3 AN: 2016

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 1 AN: 532

East Asian (EAS) AF: 0.00181 AC: 2 AN: 1106

South Asian (SAS) AF: 0.00324 AC: 2 AN: 618

European-Finnish (FIN) AF: 0.000623 AC: 1 AN: 1604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00170 AC: 12 AN: 7046

Other (OTH) AF: 0.00 AC: 0 AN: 300

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0168 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.60
PhyloP100		-0.47
Mutation Taster		=100/0	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: rs761456793; hg19: chr17-4837204; COSMIC: COSV56698611; COSMIC: COSV56698611;