chr19-55014228-T-C

Variant names:

• chr19-55014228-T-C
• rs1654412
• ENST00000310373.7:c.1717A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• 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
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 257413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083899.2. 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
	GP6	NM_016363.5	MANE Select	c.*693A>G		3_prime_UTR	Exon 8 of 8	NP_057447.5	Q9HCN6-1
	GP6	NM_001083899.2		c.1717A>G	p.Arg573Gly	missense	Exon 8 of 8	NP_001077368.2	Q9HCN6-3
	GP6	NM_001256017.2		c.*693A>G		3_prime_UTR	Exon 7 of 7	NP_001242946.2	Q9HCN6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP6	ENST00000310373.7	TSL:1	c.1717A>G	p.Arg573Gly	missense	Exon 8 of 8	ENSP00000308782.3	Q9HCN6-3
	GP6	ENST00000417454.5	TSL:1 MANE Select	c.*693A>G		3_prime_UTR	Exon 8 of 8	ENSP00000394922.1	Q9HCN6-1
	GP6	ENST00000333884.2	TSL:1	c.*693A>G		3_prime_UTR	Exon 7 of 7	ENSP00000334552.2	Q9HCN6-2

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

GnomAD2 exomes AF: 0.794 AC: 157047 AN: 197690 AF XY: 0.794

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 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

African (AFR) AF: 0.526 AC: 10064 AN: 19132

American (AMR) AF: 0.824 AC: 32684 AN: 39648

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 16731 AN: 21046

East Asian (EAS) AF: 0.798 AC: 28532 AN: 35756

South Asian (SAS) AF: 0.732 AC: 50175 AN: 68564

European-Finnish (FIN) AF: 0.871 AC: 33068 AN: 37962

Middle Eastern (MID) AF: 0.784 AC: 3280 AN: 4182

European-Non Finnish (NFE) AF: 0.827 AC: 347259 AN: 420142

Other (OTH) AF: 0.796 AC: 28007 AN: 35200

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

African (AFR) AF: 0.533 AC: 22048 AN: 41382

American (AMR) AF: 0.799 AC: 12209 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2748 AN: 3472

East Asian (EAS) AF: 0.818 AC: 4223 AN: 5162

South Asian (SAS) AF: 0.721 AC: 3477 AN: 4820

European-Finnish (FIN) AF: 0.876 AC: 9274 AN: 10592

Middle Eastern (MID) AF: 0.839 AC: 245 AN: 292

European-Non Finnish (NFE) AF: 0.832 AC: 56548 AN: 67996

Other (OTH) AF: 0.783 AC: 1648 AN: 2106

Alfa AF: 0.771 Hom.: 16321

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Platelet-type bleeding disorder 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
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
PhyloP100		-0.83
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
Mutation Taster		=100/0	polymorphism (auto)

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