8-98127615-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001145860.2(POP1):c.163C>T(p.Arg55Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: POP1 NM_001145860.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.0800

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-98127615-C-T is Pathogenic according to our data. Variant chr8-98127615-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285622.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POP1	NM_001145860.2	c.163C>T	p.Arg55Ter	stop_gained	3/16	ENST00000401707.7
POP1	NM_001145861.2	c.163C>T	p.Arg55Ter	stop_gained	3/16
POP1	NM_015029.3	c.163C>T	p.Arg55Ter	stop_gained	3/16
POP1	XM_011516801.3	c.163C>T	p.Arg55Ter	stop_gained	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POP1	ENST00000401707.7	c.163C>T	p.Arg55Ter	stop_gained	3/16	2	NM_001145860.2	P1
POP1	ENST00000349693.3	c.163C>T	p.Arg55Ter	stop_gained	3/16	1		P1
POP1	ENST00000522319.5	c.163C>T	p.Arg55Ter	stop_gained	3/5	4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251448 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152294 Hom.: 0 Cov.: 31 AF XY: 0.0000671 AC XY: 5 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000239 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Arg55*) in the POP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POP1 are known to be pathogenic (PMID: 21455487). This variant is present in population databases (rs370453487, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with POP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 285622). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.074	N
MutationTaster	Benign	1.0	A;A
Vest4		0.68
GERP RS		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs370453487; hg19: chr8-99139843; COSMIC: COSV62892375;