chr19-55015060-C-T

Variant names:

• chr19-55015060-C-T
• rs201997410
• NM_016363.5:c.881G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016363.5(GP6):​c.881G>A​(p.Arg294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,606,416 control chromosomes in the GnomAD database, including 2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: GP6 NM_016363.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.109
• Publications: 4 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=0.0063310564).
• BP6: Variant 19-55015060-C-T is Benign according to our data. Variant chr19-55015060-C-T is described in ClinVar as Benign. ClinVar VariationId is 257425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00134 (204/152310) while in subpopulation AFR AF = 0.0046 (191/41564). AF 95% confidence interval is 0.00406. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016363.5. 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.881G>A	p.Arg294Gln	missense	Exon 8 of 8	NP_057447.5	Q9HCN6-1
	GP6	NM_001256017.2		c.827G>A	p.Arg276Gln	missense	Exon 7 of 7	NP_001242946.2	Q9HCN6-2
	GP6	NM_001083899.2		c.885G>A	p.Pro295Pro	synonymous	Exon 8 of 8	NP_001077368.2	Q9HCN6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP6	ENST00000417454.5	TSL:1 MANE Select	c.881G>A	p.Arg294Gln	missense	Exon 8 of 8	ENSP00000394922.1	Q9HCN6-1
	GP6	ENST00000333884.2	TSL:1	c.827G>A	p.Arg276Gln	missense	Exon 7 of 7	ENSP00000334552.2	Q9HCN6-2
	GP6	ENST00000310373.7	TSL:1	c.885G>A	p.Pro295Pro	synonymous	Exon 8 of 8	ENSP00000308782.3	Q9HCN6-3

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000304 AC: 70 AN: 230558 AF XY: 0.000223

Gnomad AFR exome AF: 0.00469

Gnomad AMR exome AF: 0.0000921

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000167 AC: 243 AN: 1454106 Hom.: 2 Cov.: 36 AF XY: 0.000163 AC XY: 118 AN XY: 722768

African (AFR) AF: 0.00498 AC: 166 AN: 33304

American (AMR) AF: 0.000254 AC: 11 AN: 43390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39296

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84864

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000397 AC: 44 AN: 1108914

Other (OTH) AF: 0.000266 AC: 16 AN: 60060

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74482

African (AFR) AF: 0.00460 AC: 191 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000515 Hom.: 2

Bravo AF: 0.00182

ESP6500AA AF: 0.00307 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.83	T
PhyloP100		0.11
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.070
Sift	Benign	0.20	T
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.12
MVP		0.64
ClinPred		0.026	T
GERP RS		0.89
Varity_R		0.087
Mutation Taster		=98/2	polymorphism

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: rs201997410; hg19: chr19-55526428; COSMIC: COSV59980333;