8-98127622-G-A

Position:

chr8-98127622-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145860.2(POP1):c.170G>A(p.Arg57Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,920 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

POP1
NM_001145860.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

POP1 (HGNC:30129): (POP1 homolog, ribonuclease P/MRP subunit) This gene encodes the protein subunit of two different small nucleolar ribonucleoprotein complexes: the endoribonuclease for mitochondrial RNA processing complex and the ribonuclease P complex. The encoded protein is a ribonuclease that localizes to the nucleus and functions in pre-RNA processing. This protein is also an autoantigen in patients suffering from connective tissue diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

POP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.050502807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POP1	NM_001145860.2 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/16		NP_001139333.1
POP1	NM_015029.3 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/16		NP_055844.2
POP1	XM_011516801.3 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/12		XP_011515103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
POP1	ENST00000401707.7 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/16	2	NM_001145860.2	ENSP00000385787	P1
POP1	ENST00000349693.3 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/16	1		ENSP00000339529	P1
POP1	ENST00000522319.5 linkuse as main transcript	c.170G>A	p.Arg57Gln	missense_variant	3/5	4		ENSP00000428945

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251462

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000809

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.170G>A (p.R57Q) alteration is located in exon 3 (coding exon 2) of the POP1 gene. This alteration results from a G to A substitution at nucleotide position 170, causing the arginine (R) at amino acid position 57 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with POP1-related conditions. This variant is present in population databases (rs143956966, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 57 of the POP1 protein (p.Arg57Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0088

T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.66

T;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

.;L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.26

N;N;N

REVEL

Benign

0.042

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0020

.;B;B

Vest4

0.14

MVP

0.38

MPC

0.22

ClinPred

0.030

GERP RS

2.9

Varity_R

0.028

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over