rs1613662

chr19-55025227-G-Achr19-55025227-G-Cchr19-55025227-G-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.655C>T(p.Pro219Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.84 in 1,541,374 control chromosomes in the GnomAD database, including 544,761 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 0.83 (53189 hom., cov: 31)
  • Exomes 𝑓: 0.84 (491572 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.373

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=1.3788144E-6).
• BP6: Variant 19-55025227-G-A is Benign according to our data. Variant chr19-55025227-G-A is described in ClinVar as [Benign]. Clinvar id is 257422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55025227-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP6	NM_001083899.2	c.655C>T	p.Pro219Ser	missense_variant	5/8	ENST00000310373.7
GP6-AS1	XR_001754012.3	n.122-17573G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP6	ENST00000310373.7	c.655C>T	p.Pro219Ser	missense_variant	5/8	1	NM_001083899.2
GP6-AS1	ENST00000593060.5	n.156-17573G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126869 AN: 152052 Hom.: 53163 Cov.: 31

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.846

Gnomad OTH AF: 0.846

GnomAD3 exomes AF: 0.854 AC: 133645 AN: 156582 Hom.: 57422 AF XY: 0.848 AC XY: 70132 AN XY: 82720

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.922

Gnomad ASJ exome AF: 0.796

Gnomad EAS exome AF: 0.981

Gnomad SAS exome AF: 0.789

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.840 AC: 1167289 AN: 1389204 Hom.: 491572 Cov.: 30 AF XY: 0.840 AC XY: 575866 AN XY: 685906

Gnomad4 AFR exome AF: 0.764

Gnomad4 AMR exome AF: 0.918

Gnomad4 ASJ exome AF: 0.794

Gnomad4 EAS exome AF: 0.981

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.884

Gnomad4 NFE exome AF: 0.838

Gnomad4 OTH exome AF: 0.840

GnomAD4 genome AF: 0.834 AC: 126955 AN: 152170 Hom.: 53189 Cov.: 31 AF XY: 0.839 AC XY: 62391 AN XY: 74400

Gnomad4 AFR AF: 0.773

Gnomad4 AMR AF: 0.887

Gnomad4 ASJ AF: 0.795

Gnomad4 EAS AF: 0.976

Gnomad4 SAS AF: 0.786

Gnomad4 FIN AF: 0.890

Gnomad4 NFE AF: 0.846

Gnomad4 OTH AF: 0.845

Alfa AF: 0.841 Hom.: 117927

Bravo AF: 0.832

TwinsUK AF: 0.837 AC: 3105

ALSPAC AF: 0.836 AC: 3223

ESP6500AA AF: 0.779 AC: 2935

ESP6500EA AF: 0.847 AC: 6850

ExAC AF: 0.765 AC: 61765

Asia WGS AF: 0.884 AC: 3076 AN: 3478

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	This variant is associated with the following publications: (PMID: 31699788, 11571236, 22133274, 19786296, 25525159, 20227257, 21232005, 20723028, 18349091, 19278955) -

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	0.063
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.39
Dann	Benign	0.25
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0023	N
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.11	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.0080
Sift	Benign	0.76	T;T
Sift4G	Benign	0.91	T;T
Polyphen		0.0	B;B
Vest4		0.095
MPC		0.16
ClinPred		0.00058	T
GERP RS		-0.22
Varity_R		0.021
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1613662; hg19: chr19-55536595; COSMIC: COSV59979323; COSMIC: COSV59979323;