8-98123411-G-C

Variant names:

• chr8-98123411-G-C
• rs61743394
• NM_001145860.2:c.74G>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.74G>C​(p.Gly25Ala) 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 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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=0.19933072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POP1	NM_001145860.2	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 16		NP_001139333.1
POP1	NM_015029.3	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 16		NP_055844.2
POP1	XM_011516801.3	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 12		XP_011515103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POP1	ENST00000401707.7	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 16	2	NM_001145860.2	ENSP00000385787.2
POP1	ENST00000349693.3	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 16	1		ENSP00000339529.3
POP1	ENST00000522319.5	c.74G>C	p.Gly25Ala	missense_variant	Exon 2 of 5	4		ENSP00000428945.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	.;M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.15	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.89	.;P;P
Vest4		0.36, 0.34
MutPred		0.27		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.68
MPC		0.37
ClinPred		0.54	D
GERP RS		4.9
Varity_R		0.076
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61743394; hg19: chr8-99135639;