NM_016363.5:c.964A>C

Variant names:

• chr19-55014977-T-G
• rs1671152
• NM_016363.5:c.964A>C

Variant summary

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

The NM_016363.5(GP6):​c.964A>C​(p.Asn322His) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N322K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.82 (50959 hom., cov: 33)
  • Exomes 𝑓: 0.84 (520689 hom.)
• Consequence: GP6 NM_016363.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.191
• Publications: 73 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=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 VariationId is 257428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP6	NM_016363.5	MANE Select	c.964A>C	p.Asn322His	missense	Exon 8 of 8	NP_057447.5
	GP6	NM_001083899.2		c.968A>C	p.Lys323Thr	missense	Exon 8 of 8	NP_001077368.2
	GP6	NM_001256017.2		c.910A>C	p.Asn304His	missense	Exon 7 of 7	NP_001242946.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP6	ENST00000417454.5	TSL:1 MANE Select	c.964A>C	p.Asn322His	missense	Exon 8 of 8	ENSP00000394922.1
	GP6	ENST00000310373.7	TSL:1	c.968A>C	p.Lys323Thr	missense	Exon 8 of 8	ENSP00000308782.3
	GP6	ENST00000333884.2	TSL:1	c.910A>C	p.Asn304His	missense	Exon 7 of 7	ENSP00000334552.2

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

GnomAD2 exomes AF: 0.851 AC: 209926 AN: 246550 AF XY: 0.847

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 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

African (AFR) AF: 0.686 AC: 22947 AN: 33452

American (AMR) AF: 0.922 AC: 41177 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 21086 AN: 26128

East Asian (EAS) AF: 0.982 AC: 38951 AN: 39682

South Asian (SAS) AF: 0.792 AC: 68205 AN: 86168

European-Finnish (FIN) AF: 0.885 AC: 46954 AN: 53066

Middle Eastern (MID) AF: 0.799 AC: 4610 AN: 5768

European-Non Finnish (NFE) AF: 0.843 AC: 937188 AN: 1111366

Other (OTH) AF: 0.839 AC: 50652 AN: 60358

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

African (AFR) AF: 0.695 AC: 28757 AN: 41392

American (AMR) AF: 0.888 AC: 13550 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2793 AN: 3468

East Asian (EAS) AF: 0.975 AC: 5035 AN: 5162

South Asian (SAS) AF: 0.787 AC: 3797 AN: 4824

European-Finnish (FIN) AF: 0.891 AC: 9398 AN: 10552

Middle Eastern (MID) AF: 0.845 AC: 245 AN: 290

European-Non Finnish (NFE) AF: 0.851 AC: 57744 AN: 67856

Other (OTH) AF: 0.836 AC: 1763 AN: 2110

Alfa AF: 0.838 Hom.: 183722

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Platelet-type bleeding disorder 11 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.19
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
Varity_R		0.032
gMVP		0.032
Mutation Taster		=100/0	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: rs1671152; hg19: chr19-55526345; COSMIC: COSV59977360;