19-55014218-C-T

Position:

• chr19-55014218-C-T

Variant summary

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

The ENST00000310373.7(GP6):​c.1727G>A​(p.Arg576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 793,436 control chromosomes in the GnomAD database, including 1,362 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 0.065 (387 hom., cov: 32)
  • Exomes 𝑓: 0.052 (975 hom.)
• Consequence: GP6 ENST00000310373.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.266

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=0.0018121004).
• BP6: Variant 19-55014218-C-T is Benign according to our data. Variant chr19-55014218-C-T is described in ClinVar as [Benign]. Clinvar id is 257414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP6	NM_001083899.2	c.1727G>A	p.Arg576Lys	missense_variant	8/8	ENST00000310373.7	NP_001077368.2
GP6-AS1	XR_001754012.3	n.121+7754C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP6	ENST00000310373.7	c.1727G>A	p.Arg576Lys	missense_variant	8/8	1	NM_001083899.2	ENSP00000308782
GP6-AS1	ENST00000593060.5	n.155+7754C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9878 AN: 152074 Hom.: 388 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0565

GnomAD3 exomes AF: 0.0519 AC: 9410 AN: 181162 Hom.: 296 AF XY: 0.0530 AC XY: 5259 AN XY: 99258

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.0396

Gnomad EAS exome AF: 0.0544

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0622

Gnomad NFE exome AF: 0.0507

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0518 AC: 33223 AN: 641244 Hom.: 975 Cov.: 8 AF XY: 0.0524 AC XY: 18133 AN XY: 345768

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.0447

Gnomad4 SAS exome AF: 0.0624

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.0502

Gnomad4 OTH exome AF: 0.0517

GnomAD4 genome AF: 0.0649 AC: 9879 AN: 152192 Hom.: 387 Cov.: 32 AF XY: 0.0642 AC XY: 4779 AN XY: 74400

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0438

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.0556

Gnomad4 SAS AF: 0.0647

Gnomad4 FIN AF: 0.0562

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0311 Hom.: 31

Bravo AF: 0.0669

TwinsUK AF: 0.0445 AC: 165

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.0810 AC: 310

ESP6500EA AF: 0.0444 AC: 359

ExAC AF: 0.0508 AC: 6028

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.87
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.076	T
Polyphen		0.22	B
Vest4		0.053
MPC		0.22
ClinPred		0.013	T
GERP RS		0.23
gMVP		0.034

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: rs10418074; hg19: chr19-55525586; COSMIC: COSV59977213; COSMIC: COSV59977213;