rs769183311

chr8-98140867-C-Gchr8-98140867-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001145860.2(POP1):c.1573C>G(p.Pro525Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P525S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-98140867-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 393588.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.108685404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POP1	NM_001145860.2	c.1573C>G	p.Pro525Ala	missense_variant	11/16	ENST00000401707.7
POP1	NM_001145861.2	c.1573C>G	p.Pro525Ala	missense_variant	11/16
POP1	NM_015029.3	c.1573C>G	p.Pro525Ala	missense_variant	11/16
POP1	XM_011516801.3	c.1573C>G	p.Pro525Ala	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POP1	ENST00000401707.7	c.1573C>G	p.Pro525Ala	missense_variant	11/16	2	NM_001145860.2	P1
POP1	ENST00000349693.3	c.1573C>G	p.Pro525Ala	missense_variant	11/16	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251356 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135870

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727170

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000511 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Benign	0.74
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.15
Sift	Benign	0.045	D;D
Sift4G	Benign	0.30	T;T
Polyphen		0.015	B;B
Vest4		0.17
MutPred		0.29		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.34
MPC		0.20
ClinPred		0.12	T
GERP RS		-0.58
Varity_R		0.16
gMVP		0.25

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: rs769183311; hg19: chr8-99153095;