1-156903934-C-T

Variant names:

• chr1-156903934-C-T
• rs186465653
• NM_001080471.3:c.8C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001353682.2(PEAR1):​c.-331C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: PEAR1 NM_001353682.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.197

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020579904).
• BP6: Variant 1-156903934-C-T is Benign according to our data. Variant chr1-156903934-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2271187.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEAR1	NM_001080471.3	c.8C>T	p.Pro3Leu	missense_variant	Exon 2 of 23	ENST00000292357.8	NP_001073940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEAR1	ENST00000292357.8	c.8C>T	p.Pro3Leu	missense_variant	Exon 2 of 23	5	NM_001080471.3	ENSP00000292357.7
PEAR1	ENST00000338302.7	c.8C>T	p.Pro3Leu	missense_variant	Exon 3 of 24	5		ENSP00000344465.3
PEAR1	ENST00000455314.5	c.8C>T	p.Pro3Leu	missense_variant	Exon 2 of 6	2		ENSP00000389742.1
PEAR1	ENST00000444016.5	n.8C>T		non_coding_transcript_exon_variant	Exon 2 of 7	3		ENSP00000397870.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251302 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461654 Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000385 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 03, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	3.0
DANN	Benign	0.82
DEOGEN2	Benign	0.0044	T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.52	.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.45	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	B;.;B
Vest4		0.062
MVP		0.17
MPC		0.16
ClinPred		0.065	T
GERP RS		2.2
Varity_R		0.034
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs186465653; hg19: chr1-156873726;