19-55015005-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083899.2(GP6):c.940C>G(p.Pro314Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 151,900 control chromosomes in the GnomAD database, including 19,636 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P314P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.48 (19636 hom., cov: 33)
  • Exomes 𝑓: 0.57 (241399 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.277

Genes affected

GP6 (HGNC:14388): (glycoprotein VI platelet) This gene encodes a platelet membrane glycoprotein of the immunoglobulin superfamily. The encoded protein is a receptor for collagen and plays a critical role in collagen-induced platelet aggregation and thrombus formation. The encoded protein forms a complex with the Fc receptor gamma-chain that initiates the platelet activation signaling cascade upon collagen binding. Mutations in this gene are a cause of platelet-type bleeding disorder-11 (BDPLT11). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

GP6-AS1 (HGNC:55305): (GP6 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.248344E-5).
• BP6: Variant 19-55015005-G-C is Benign according to our data. Variant chr19-55015005-G-C is described in ClinVar as [Benign]. Clinvar id is 257426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55015005-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP6	NM_001083899.2	c.940C>G	p.Pro314Ala	missense_variant	8/8	ENST00000310373.7
GP6-AS1	XR_001754012.3	n.121+8541G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP6	ENST00000310373.7	c.940C>G	p.Pro314Ala	missense_variant	8/8	1	NM_001083899.2
GP6-AS1	ENST00000593060.5	n.155+8541G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73233 AN: 151784 Hom.: 19644 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.507

GnomAD3 exomes AF: 0.520 AC: 126039 AN: 242548 Hom.: 34560 AF XY: 0.525 AC XY: 69394 AN XY: 132098

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.465

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.602

Gnomad OTH exome AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.569 AC: 829184 AN: 1458520 Hom.: 241399 Cov.: 46 AF XY: 0.567 AC XY: 411367 AN XY: 725506

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.252

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.622

Gnomad4 NFE exome AF: 0.600

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.482 AC: 73245 AN: 151900 Hom.: 19636 Cov.: 33 AF XY: 0.483 AC XY: 35857 AN XY: 74266

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.547

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.504

Alfa AF: 0.566 Hom.: 7576

Bravo AF: 0.466

TwinsUK AF: 0.599 AC: 2221

ALSPAC AF: 0.596 AC: 2296

ESP6500AA AF: 0.241 AC: 916

ESP6500EA AF: 0.601 AC: 4939

ExAC AF: 0.511 AC: 61627

Asia WGS AF: 0.367 AC: 1278 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

GP6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 2020

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

Platelet-type bleeding disorder 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Uncertain	0.98
Eigen	Benign	0.084
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.54	D
MetaRNN	Benign	0.000052	T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.098
Sift	Benign	0.34	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.61
ClinPred		0.022	T
GERP RS		2.6
gMVP		0.041

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: rs2304166; hg19: chr19-55526373; COSMIC: COSV59977140;