chr19-55014977-T-G

Position:

• chr19-55014977-T-G

Variant summary

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

The NM_001083899.2(GP6):​c.968A>C​(p.Lys323Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,612,488 control chromosomes in the GnomAD database, including 571,648 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. K323S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (50959 hom., cov: 33)
  • Exomes 𝑓: 0.84 (520689 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.191

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=1.233405E-6).
• BP6: Variant 19-55014977-T-G is Benign according to our data. Variant chr19-55014977-T-G is described in ClinVar as [Benign]. Clinvar id is 257428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55014977-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP6	NM_001083899.2	c.968A>C	p.Lys323Thr	missense_variant	8/8	ENST00000310373.7
GP6-AS1	XR_001754012.3	n.121+8513T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP6	ENST00000310373.7	c.968A>C	p.Lys323Thr	missense_variant	8/8	1	NM_001083899.2
GP6-AS1	ENST00000593060.5	n.155+8513T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123699 AN: 151706 Hom.: 50937 Cov.: 33

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.846

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.836

GnomAD3 exomes AF: 0.851 AC: 209926 AN: 246550 Hom.: 89970 AF XY: 0.847 AC XY: 113417 AN XY: 133912

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.927

Gnomad ASJ exome AF: 0.811

Gnomad EAS exome AF: 0.984

Gnomad SAS exome AF: 0.789

Gnomad FIN exome AF: 0.884

Gnomad NFE exome AF: 0.845

Gnomad OTH exome AF: 0.845

GnomAD4 exome AF: 0.843 AC: 1231770 AN: 1460662 Hom.: 520689 Cov.: 56 AF XY: 0.842 AC XY: 612082 AN XY: 726582

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.922

Gnomad4 ASJ exome AF: 0.807

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.792

Gnomad4 FIN exome AF: 0.885

Gnomad4 NFE exome AF: 0.843

Gnomad4 OTH exome AF: 0.839

GnomAD4 genome AF: 0.815 AC: 123778 AN: 151826 Hom.: 50959 Cov.: 33 AF XY: 0.819 AC XY: 60757 AN XY: 74206

Gnomad4 AFR AF: 0.695

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.805

Gnomad4 EAS AF: 0.975

Gnomad4 SAS AF: 0.787

Gnomad4 FIN AF: 0.891

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.836

Alfa AF: 0.848 Hom.: 85038

Bravo AF: 0.810

TwinsUK AF: 0.846 AC: 3138

ALSPAC AF: 0.843 AC: 3250

ESP6500AA AF: 0.690 AC: 2707

ESP6500EA AF: 0.849 AC: 7026

ExAC AF: 0.842 AC: 101730

Asia WGS AF: 0.882 AC: 3064 AN: 3476

EpiCase AF: 0.843

EpiControl AF: 0.841

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Platelet-type bleeding disorder 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.37
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0011	N
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.19
ClinPred		0.0023	T
GERP RS		2.6
gMVP		0.032

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: rs1671152; hg19: chr19-55526345; COSMIC: COSV59977360;