8-98127649-T-C

Position:

• chr8-98127649-T-C

Variant summary

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

The NM_001145860.2(POP1):​c.197T>C​(p.Leu66Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0450

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=0.07841417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POP1	NM_001145860.2	c.197T>C	p.Leu66Pro	missense_variant	3/16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2	c.197T>C	p.Leu66Pro	missense_variant	3/16		NP_001139333.1
POP1	NM_015029.3	c.197T>C	p.Leu66Pro	missense_variant	3/16		NP_055844.2
POP1	XM_011516801.3	c.197T>C	p.Leu66Pro	missense_variant	3/12		XP_011515103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POP1	ENST00000401707.7	c.197T>C	p.Leu66Pro	missense_variant	3/16	2	NM_001145860.2	ENSP00000385787	P1
POP1	ENST00000349693.3	c.197T>C	p.Leu66Pro	missense_variant	3/16	1		ENSP00000339529	P1
POP1	ENST00000522319.5	c.197T>C	p.Leu66Pro	missense_variant	3/5	4		ENSP00000428945

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.197T>C (p.L66P) alteration is located in exon 3 (coding exon 2) of the POP1 gene. This alteration results from a T to C substitution at nucleotide position 197, causing the leucine (L) at amino acid position 66 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.68
DEOGEN2	Benign	0.0067	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.31	T;.;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	.;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.0090
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.066, 0.062
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.25
MPC		0.30
ClinPred		0.026	T
GERP RS		0.83
Varity_R		0.053
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-99139877;