Genetic Variant GP6:p.Pro219Thr (chr19-55025227-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016363.5(GP6):c.655C>A(p.Pro219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P219S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GP6
NM_016363.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.373

Publications

122 publications found

Variant links:

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 links:

GP6-AS1 (HGNC:55305): (GP6 antisense RNA 1)

GP6-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041596472).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GP6	NM_016363.5	MANE Select	c.655C>A	p.Pro219Thr	missense	Exon 5 of 8	NP_057447.5
GP6	NM_001083899.2		c.655C>A	p.Pro219Thr	missense	Exon 5 of 8	NP_001077368.2
GP6	NM_001256017.2		c.610+2351C>A		intron	N/A	NP_001242946.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GP6	ENST00000417454.5	TSL:1 MANE Select	c.655C>A	p.Pro219Thr	missense	Exon 5 of 8	ENSP00000394922.1
GP6	ENST00000310373.7	TSL:1	c.655C>A	p.Pro219Thr	missense	Exon 5 of 8	ENSP00000308782.3
GP6	ENST00000333884.2	TSL:1	c.610+2351C>A		intron	N/A	ENSP00000334552.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1391306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686884

African (AFR)

AF:

0.00

AC:

AN:

31440

American (AMR)

AF:

0.00

AC:

AN:

35772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25106

East Asian (EAS)

AF:

0.00

AC:

AN:

35724

South Asian (SAS)

AF:

0.00

AC:

AN:

79088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071334

Other (OTH)

AF:

0.00

AC:

AN:

57810

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.019

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.018

M_CAP

Benign

0.011

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.37

PrimateAI

Benign

0.29

PROVEAN

Benign

1.2

REVEL

Benign

0.010

Sift

Benign

1.0

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.11

MutPred

0.19

Gain of phosphorylation at P219 (P = 0.0337)

MVP

0.19

MPC

0.18

ClinPred

0.024

GERP RS

-0.22

Varity_R

0.026

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over