19-55014228-T-C

Position:

• chr19-55014228-T-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.1717A>G​(p.Arg573Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 833,636 control chromosomes in the GnomAD database, including 266,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43469 hom., cov: 31)
  • Exomes 𝑓: 0.81 (223305 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.833

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=8.8510706E-7).
• BP6: Variant 19-55014228-T-C is Benign according to our data. Variant chr19-55014228-T-C is described in ClinVar as [Benign]. Clinvar id is 257413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55014228-T-C 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	Protein	UniProt
GP6	NM_001083899.2	c.1717A>G	p.Arg573Gly	missense_variant	8/8	ENST00000310373.7	NP_001077368.2
GP6-AS1	XR_001754012.3	n.121+7764T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP6	ENST00000310373.7	c.1717A>G	p.Arg573Gly	missense_variant	8/8	1	NM_001083899.2	ENSP00000308782
GP6-AS1	ENST00000593060.5	n.155+7764T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113073 AN: 151886 Hom.: 43463 Cov.: 31

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.876

Gnomad MID AF: 0.841

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.785

GnomAD3 exomes AF: 0.794 AC: 157047 AN: 197690 Hom.: 63040 AF XY: 0.794 AC XY: 86217 AN XY: 108620

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.795

Gnomad EAS exome AF: 0.832

Gnomad SAS exome AF: 0.728

Gnomad FIN exome AF: 0.869

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.807 AC: 549800 AN: 681632 Hom.: 223305 Cov.: 8 AF XY: 0.805 AC XY: 294962 AN XY: 366394

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.824

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.732

Gnomad4 FIN exome AF: 0.871

Gnomad4 NFE exome AF: 0.827

Gnomad4 OTH exome AF: 0.796

GnomAD4 genome AF: 0.744 AC: 113122 AN: 152004 Hom.: 43469 Cov.: 31 AF XY: 0.748 AC XY: 55570 AN XY: 74314

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.818

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.876

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.783

Alfa AF: 0.765 Hom.: 8377

Bravo AF: 0.730

TwinsUK AF: 0.821 AC: 3043

ALSPAC AF: 0.817 AC: 3149

ESP6500AA AF: 0.531 AC: 2026

ESP6500EA AF: 0.829 AC: 6725

ExAC AF: 0.769 AC: 90576

Asia WGS AF: 0.746 AC: 2595 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.3
DANN	Benign	0.87
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0088	N
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Polyphen		0.60	P
Vest4		0.068
MPC		0.33
ClinPred		0.0029	T
GERP RS		-0.47
gMVP		0.022

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: rs1654412; hg19: chr19-55525596; COSMIC: COSV59976643; COSMIC: COSV59976643;