1-156905392-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001080471.3(PEAR1):c.275A>G(p.His92Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PEAR1 NM_001080471.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.938

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08539343).
• BP6: Variant 1-156905392-A-G is Benign according to our data. Variant chr1-156905392-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2409176.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEAR1	NM_001080471.3	c.275A>G	p.His92Arg	missense_variant	4/23	ENST00000292357.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEAR1	ENST00000292357.8	c.275A>G	p.His92Arg	missense_variant	4/23	5	NM_001080471.3	P1
PEAR1	ENST00000338302.7	c.275A>G	p.His92Arg	missense_variant	5/24	5		P1
PEAR1	ENST00000455314.5	c.275A>G	p.His92Arg	missense_variant	4/6	2
PEAR1	ENST00000444016.5	c.*96A>G		3_prime_UTR_variant, NMD_transcript_variant	5/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244578 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456484 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.0040
Dann	Benign	0.37
DEOGEN2	Benign	0.0024	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.032	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-1.1	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.63	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.14
MutPred		0.61		Gain of MoRF binding (P = 0.0154);Gain of MoRF binding (P = 0.0154);Gain of MoRF binding (P = 0.0154);
MVP		0.25
MPC		0.19
ClinPred		0.021	T
GERP RS		-4.8
Varity_R		0.056
gMVP		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772409495; hg19: chr1-156875184;