8-98123351-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145860.2(POP1):c.14A>G(p.Lys5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12680429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POP1	NM_001145860.2	c.14A>G	p.Lys5Arg	missense_variant	2/16	ENST00000401707.7
POP1	NM_001145861.2	c.14A>G	p.Lys5Arg	missense_variant	2/16
POP1	NM_015029.3	c.14A>G	p.Lys5Arg	missense_variant	2/16
POP1	XM_011516801.3	c.14A>G	p.Lys5Arg	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POP1	ENST00000401707.7	c.14A>G	p.Lys5Arg	missense_variant	2/16	2	NM_001145860.2	P1
POP1	ENST00000349693.3	c.14A>G	p.Lys5Arg	missense_variant	2/16	1		P1
POP1	ENST00000522319.5	c.14A>G	p.Lys5Arg	missense_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461582 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 28, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 5 of the POP1 protein (p.Lys5Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POP1-related conditions. 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 arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0094	T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.090
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0090	.;B;B
Vest4		0.097, 0.094
MutPred		0.14		Loss of ubiquitination at K5 (P = 0.063);Loss of ubiquitination at K5 (P = 0.063);Loss of ubiquitination at K5 (P = 0.063);
MVP		0.52
MPC		0.19
ClinPred		0.57	D
GERP RS		3.5
Varity_R		0.030
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1051371484; hg19: chr8-99135579;