19-55014288-T-G

Variant names:

• chr19-55014288-T-G
• rs201681535
• ENST00000310373.7:c.1657A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083899.2(GP6):​c.1657A>C​(p.Asn553His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000792 in 1,262,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. N553D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: GP6 NM_001083899.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.220
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15776971).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083899.2. 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.*633A>C		3_prime_UTR	Exon 8 of 8	NP_057447.5	Q9HCN6-1
	GP6	NM_001083899.2		c.1657A>C	p.Asn553His	missense	Exon 8 of 8	NP_001077368.2	Q9HCN6-3
	GP6	NM_001256017.2		c.*633A>C		3_prime_UTR	Exon 7 of 7	NP_001242946.2	Q9HCN6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP6	ENST00000310373.7	TSL:1	c.1657A>C	p.Asn553His	missense	Exon 8 of 8	ENSP00000308782.3	Q9HCN6-3
	GP6	ENST00000417454.5	TSL:1 MANE Select	c.*633A>C		3_prime_UTR	Exon 8 of 8	ENSP00000394922.1	Q9HCN6-1
	GP6	ENST00000333884.2	TSL:1	c.*633A>C		3_prime_UTR	Exon 7 of 7	ENSP00000334552.2	Q9HCN6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.92e-7 AC: 1 AN: 1262268 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 637862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29704

American (AMR) AF: 0.00 AC: 0 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24886

East Asian (EAS) AF: 0.00 AC: 0 AN: 38744

South Asian (SAS) AF: 0.00 AC: 0 AN: 82368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 934830

Other (OTH) AF: 0.00 AC: 0 AN: 54016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.86	T
PhyloP100		0.22
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.040
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.16
MutPred		0.21		Loss of MoRF binding (P = 0.1038)
MVP		0.15
MPC		0.59
ClinPred		0.45	T
GERP RS		0.14
gMVP		0.016
Mutation Taster		=99/1	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: rs201681535; hg19: chr19-55525656;