8-98127673-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001145860.2(POP1):c.221A>G(p.Gln74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,614,168 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.44

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026729703).
• BP6: Variant 8-98127673-A-G is Benign according to our data. Variant chr8-98127673-A-G is described in ClinVar as [Benign]. Clinvar id is 709344.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00395 (602/152306) while in subpopulation AFR AF= 0.014 (582/41550). AF 95% confidence interval is 0.0131. There are 5 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POP1	NM_001145860.2	c.221A>G	p.Gln74Arg	missense_variant	3/16	ENST00000401707.7
POP1	NM_001145861.2	c.221A>G	p.Gln74Arg	missense_variant	3/16
POP1	NM_015029.3	c.221A>G	p.Gln74Arg	missense_variant	3/16
POP1	XM_011516801.3	c.221A>G	p.Gln74Arg	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POP1	ENST00000401707.7	c.221A>G	p.Gln74Arg	missense_variant	3/16	2	NM_001145860.2	P1
POP1	ENST00000349693.3	c.221A>G	p.Gln74Arg	missense_variant	3/16	1		P1
POP1	ENST00000522319.5	c.221A>G	p.Gln74Arg	missense_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152188 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00113 AC: 285 AN: 251476 Hom.: 3 AF XY: 0.000839 AC XY: 114 AN XY: 135908

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.000405

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: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1461862 Hom.: 1 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 727232

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00395 AC: 602 AN: 152306 Hom.: 5 Cov.: 31 AF XY: 0.00369 AC XY: 275 AN XY: 74478

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00467

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.65	T;.;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.86	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.038
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.52	T;T;T
Polyphen		0.72	.;P;P
Vest4		0.18
MVP		0.55
MPC		0.28
ClinPred		0.029	T
GERP RS		2.2
Varity_R		0.064
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: rs141161667; hg19: chr8-99139901;