rs822442

Positions:

• chr1-156913423-C-A
• chr1-156913423-C-T

Variant summary

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

The NM_001080471.3(PEAR1):​c.2544C>A​(p.Asn848Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,822 control chromosomes in the GnomAD database, including 14,677 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2082 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12595 hom.)
• Consequence: PEAR1 NM_001080471.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.632

Genes affected

PEAR1 (HGNC:33631): (platelet endothelial aggregation receptor 1) PEAR1 is a platelet receptor that signals upon the formation of platelet-platelet contacts independent of platelet activation and secondary to platelet aggregation (Nanda et al., 2005 [PubMed 15851471]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037869513).
• BP6: Variant 1-156913423-C-A is Benign according to our data. Variant chr1-156913423-C-A is described in ClinVar as [Benign]. Clinvar id is 1243276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEAR1	NM_001080471.3	c.2544C>A	p.Asn848Lys	missense_variant	20/23	ENST00000292357.8	NP_001073940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEAR1	ENST00000292357.8	c.2544C>A	p.Asn848Lys	missense_variant	20/23	5	NM_001080471.3	ENSP00000292357	P1
PEAR1	ENST00000338302.7	c.2544C>A	p.Asn848Lys	missense_variant	21/24	5		ENSP00000344465	P1
PEAR1	ENST00000469390.5	n.2272C>A		non_coding_transcript_exon_variant	15/18	2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23856 AN: 152108 Hom.: 2077 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.142 AC: 35571 AN: 250654 Hom.: 3011 AF XY: 0.140 AC XY: 19023 AN XY: 135650

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.122 AC: 178088 AN: 1461596 Hom.: 12595 Cov.: 34 AF XY: 0.123 AC XY: 89381 AN XY: 727120

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.157 AC: 23873 AN: 152226 Hom.: 2082 Cov.: 33 AF XY: 0.160 AC XY: 11896 AN XY: 74432

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.146

Alfa AF: 0.126 Hom.: 718

Bravo AF: 0.158

TwinsUK AF: 0.104 AC: 387

ALSPAC AF: 0.0947 AC: 365

ESP6500AA AF: 0.227 AC: 1001

ESP6500EA AF: 0.115 AC: 992

ExAC AF: 0.144 AC: 17459

Asia WGS AF: 0.234 AC: 813 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.104

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 29407631) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.6
DANN	Benign	0.68
DEOGEN2	Benign	0.0078	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.27	.;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.12
Sift	Benign	0.81	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.057	B;B
Vest4		0.047
MutPred		0.11		Gain of glycosylation at N848 (P = 0.0055);Gain of glycosylation at N848 (P = 0.0055);
MPC		0.18
ClinPred		0.0036	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs822442; hg19: chr1-156883215; COSMIC: COSV52770876; COSMIC: COSV52770876;