8-98123347-G-A

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.10G>A(p.Ala4Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00341 in 1,613,516 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (77 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.58

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=0.006253153).
• BP6: Variant 8-98123347-G-A is Benign according to our data. Variant chr8-98123347-G-A is described in ClinVar as [Benign]. Clinvar id is 724459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00192 (292/152214) while in subpopulation SAS AF= 0.0327 (157/4806). AF 95% confidence interval is 0.0285. There are 3 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POP1	NM_001145860.2	c.10G>A	p.Ala4Thr	missense_variant	2/16	ENST00000401707.7
POP1	NM_001145861.2	c.10G>A	p.Ala4Thr	missense_variant	2/16
POP1	NM_015029.3	c.10G>A	p.Ala4Thr	missense_variant	2/16
POP1	XM_011516801.3	c.10G>A	p.Ala4Thr	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POP1	ENST00000401707.7	c.10G>A	p.Ala4Thr	missense_variant	2/16	2	NM_001145860.2	P1
POP1	ENST00000349693.3	c.10G>A	p.Ala4Thr	missense_variant	2/16	1		P1
POP1	ENST00000522319.5	c.10G>A	p.Ala4Thr	missense_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152096 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00556 AC: 1397 AN: 251424 Hom.: 26 AF XY: 0.00711 AC XY: 966 AN XY: 135894

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0354

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00356 AC: 5208 AN: 1461302 Hom.: 77 Cov.: 31 AF XY: 0.00450 AC XY: 3272 AN XY: 727006

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00938

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0343

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.00436

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152214 Hom.: 3 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74426

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0327

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00587 AC: 713

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00142

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.031	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;.;T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	0.57	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.49, 0.49
MVP		0.75
MPC		0.72
ClinPred		0.053	T
GERP RS		4.9
Varity_R		0.41
gMVP		0.55

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: rs145484648; hg19: chr8-99135575;