ENST00000310373.7:c.940C>G

Variant names:

• chr19-55015005-G-C
• rs2304166
• ENST00000310373.7:c.940C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000310373.7(GP6):​c.940C>G​(p.Pro314Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 151,900 control chromosomes in the GnomAD database, including 19,636 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P314P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.48 (19636 hom., cov: 33)
  • Exomes 𝑓: 0.57 (241399 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP6 ENST00000310373.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.277
• Publications: 24 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=5.248344E-5).
• BP6: Variant 19-55015005-G-C is Benign according to our data. Variant chr19-55015005-G-C is described in ClinVar as Benign. ClinVar VariationId is 257426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000310373.7. 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.936C>G	p.Leu312Leu	synonymous	Exon 8 of 8	NP_057447.5	Q9HCN6-1
	GP6	NM_001083899.2		c.940C>G	p.Pro314Ala	missense	Exon 8 of 8	NP_001077368.2	Q9HCN6-3
	GP6	NM_001256017.2		c.882C>G	p.Leu294Leu	synonymous	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.940C>G	p.Pro314Ala	missense	Exon 8 of 8	ENSP00000308782.3	Q9HCN6-3
	GP6	ENST00000417454.5	TSL:1 MANE Select	c.936C>G	p.Leu312Leu	synonymous	Exon 8 of 8	ENSP00000394922.1	Q9HCN6-1
	GP6	ENST00000333884.2	TSL:1	c.882C>G	p.Leu294Leu	synonymous	Exon 7 of 7	ENSP00000334552.2	Q9HCN6-2

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73233 AN: 151784 Hom.: 19644 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.520 AC: 126039 AN: 242548 AF XY: 0.525

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.602

Gnomad OTH exome AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.569 AC: 829184 AN: 1458520 Hom.: 241399 Cov.: 46 AF XY: 0.567 AC XY: 411367 AN XY: 725506

African (AFR) AF: 0.244 AC: 8129 AN: 33298

American (AMR) AF: 0.496 AC: 22055 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14066 AN: 26084

East Asian (EAS) AF: 0.252 AC: 9963 AN: 39592

South Asian (SAS) AF: 0.463 AC: 39802 AN: 85980

European-Finnish (FIN) AF: 0.622 AC: 32973 AN: 52972

Middle Eastern (MID) AF: 0.523 AC: 3004 AN: 5748

European-Non Finnish (NFE) AF: 0.600 AC: 666578 AN: 1110144

Other (OTH) AF: 0.541 AC: 32614 AN: 60236

GnomAD4 genome AF: 0.482 AC: 73245 AN: 151900 Hom.: 19636 Cov.: 33 AF XY: 0.483 AC XY: 35857 AN XY: 74266

African (AFR) AF: 0.254 AC: 10517 AN: 41416

American (AMR) AF: 0.531 AC: 8103 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1892 AN: 3462

East Asian (EAS) AF: 0.234 AC: 1211 AN: 5172

South Asian (SAS) AF: 0.438 AC: 2109 AN: 4816

European-Finnish (FIN) AF: 0.628 AC: 6637 AN: 10576

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.604 AC: 41018 AN: 67876

Other (OTH) AF: 0.504 AC: 1064 AN: 2112

Alfa AF: 0.566 Hom.: 7576

Bravo AF: 0.466

TwinsUK AF: 0.599 AC: 2221

ALSPAC AF: 0.596 AC: 2296

ESP6500AA AF: 0.241 AC: 916

ESP6500EA AF: 0.601 AC: 4939

ExAC AF: 0.511 AC: 61627

Asia WGS AF: 0.367 AC: 1278 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GP6-related disorder (1)
-	-	1	Platelet-type bleeding disorder 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Uncertain	0.98
Eigen	Benign	0.084
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.54	D
MetaRNN	Benign	0.000052	T
MetaSVM	Benign	-1.2	T
PhyloP100		0.28
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.098
Sift	Benign	0.34	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.61
ClinPred		0.022	T
GERP RS		2.6
gMVP		0.041
Mutation Taster		=99/1	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: rs2304166; hg19: chr19-55526373; COSMIC: COSV59977140;