19-55014450-C-T

Position:

• chr19-55014450-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083899.2(GP6):​c.1495G>A​(p.Gly499Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,613,282 control chromosomes in the GnomAD database, including 744 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 0.023 (60 hom., cov: 33)
  • Exomes 𝑓: 0.028 (684 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0460

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=0.0024445355).
• BP6: Variant 19-55014450-C-T is Benign according to our data. Variant chr19-55014450-C-T is described in ClinVar as [Benign]. Clinvar id is 257412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55014450-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3512/152222) while in subpopulation NFE AF= 0.0327 (2224/68012). AF 95% confidence interval is 0.0316. There are 60 homozygotes in gnomad4. There are 1729 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP6	NM_001083899.2	c.1495G>A	p.Gly499Ser	missense_variant	8/8	ENST00000310373.7	NP_001077368.2
GP6-AS1	XR_001754012.3	n.121+7986C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP6	ENST00000310373.7	c.1495G>A	p.Gly499Ser	missense_variant	8/8	1	NM_001083899.2	ENSP00000308782
GP6-AS1	ENST00000593060.5	n.155+7986C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3511 AN: 152104 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0274

GnomAD3 exomes AF: 0.0245 AC: 6105 AN: 249568 Hom.: 108 AF XY: 0.0249 AC XY: 3367 AN XY: 135402

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0280 AC: 40873 AN: 1461060 Hom.: 684 Cov.: 32 AF XY: 0.0276 AC XY: 20071 AN XY: 726906

Gnomad4 AFR exome AF: 0.00400

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0408

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00617

Gnomad4 FIN exome AF: 0.0377

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0231 AC: 3512 AN: 152222 Hom.: 60 Cov.: 33 AF XY: 0.0232 AC XY: 1729 AN XY: 74410

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0285

Alfa AF: 0.0316 Hom.: 150

Bravo AF: 0.0220

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0296 AC: 114

ESP6500AA AF: 0.00486 AC: 19

ESP6500EA AF: 0.0346 AC: 287

ExAC AF: 0.0250 AC: 3026

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0354

EpiControl AF: 0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

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	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.40
DANN	Benign	0.34
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0010	N
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.16
ClinPred		0.0051	T
GERP RS		0.49
gMVP		0.024

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: rs41275822; hg19: chr19-55525818; COSMIC: COSV59978744; COSMIC: COSV59978744;