rs2304167

chr19-55015713-C-T

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.745G>A(p.Ala249Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,565,964 control chromosomes in the GnomAD database, including 508,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43220 hom., cov: 30)
  • Exomes 𝑓: 0.81 (464954 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.77

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=1.0152187E-6).
• BP6: Variant 19-55015713-C-T is Benign according to our data. Variant chr19-55015713-C-T is described in ClinVar as [Benign]. Clinvar id is 257424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55015713-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP6	NM_001083899.2	c.745G>A	p.Ala249Thr	missense_variant	7/8	ENST00000310373.7
GP6-AS1	XR_001754012.3	n.121+9249C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP6	ENST00000310373.7	c.745G>A	p.Ala249Thr	missense_variant	7/8	1	NM_001083899.2
GP6-AS1	ENST00000593060.5	n.155+9249C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112611 AN: 151798 Hom.: 43216 Cov.: 30

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.876

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.783

GnomAD3 exomes AF: 0.797 AC: 198230 AN: 248688 Hom.: 80048 AF XY: 0.797 AC XY: 107483 AN XY: 134862

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.797

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.825

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.808 AC: 1143233 AN: 1414048 Hom.: 464954 Cov.: 27 AF XY: 0.808 AC XY: 571058 AN XY: 706660

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.825

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.731

Gnomad4 FIN exome AF: 0.871

Gnomad4 NFE exome AF: 0.821

Gnomad4 OTH exome AF: 0.796

GnomAD4 genome AF: 0.742 AC: 112658 AN: 151916 Hom.: 43220 Cov.: 30 AF XY: 0.745 AC XY: 55329 AN XY: 74266

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.876

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.781

Alfa AF: 0.810 Hom.: 92965

Bravo AF: 0.727

TwinsUK AF: 0.821 AC: 3043

ALSPAC AF: 0.817 AC: 3147

ESP6500AA AF: 0.524 AC: 2097

ESP6500EA AF: 0.830 AC: 6939

ExAC AF: 0.788 AC: 95263

Asia WGS AF: 0.748 AC: 2601 AN: 3478

EpiCase AF: 0.824

EpiControl AF: 0.827

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.57
Dann	Benign	0.64
DEOGEN2	Benign	0.026	T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.012	N
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.90	L;L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.98	T;T;T
Sift4G	Benign	0.40	T;D;T
Polyphen		0.0010	B;B;B
Vest4		0.015
MPC		0.19
ClinPred		0.0048	T
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.15

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: rs2304167; hg19: chr19-55527081; COSMIC: COSV59979310;