8-98123411-G-A

Position:

• chr8-98123411-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145860.2(POP1):​c.74G>A​(p.Gly25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,614,098 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (4 hom.)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032549113).
• BP6: Variant 8-98123411-G-A is Benign according to our data. Variant chr8-98123411-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1519057.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000683 (104/152290) while in subpopulation SAS AF= 0.00124 (6/4828). AF 95% confidence interval is 0.000834. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POP1	NM_001145860.2	c.74G>A	p.Gly25Asp	missense_variant	2/16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2	c.74G>A	p.Gly25Asp	missense_variant	2/16		NP_001139333.1
POP1	NM_015029.3	c.74G>A	p.Gly25Asp	missense_variant	2/16		NP_055844.2
POP1	XM_011516801.3	c.74G>A	p.Gly25Asp	missense_variant	2/12		XP_011515103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POP1	ENST00000401707.7	c.74G>A	p.Gly25Asp	missense_variant	2/16	2	NM_001145860.2	ENSP00000385787	P1
POP1	ENST00000349693.3	c.74G>A	p.Gly25Asp	missense_variant	2/16	1		ENSP00000339529	P1
POP1	ENST00000522319.5	c.74G>A	p.Gly25Asp	missense_variant	2/5	4		ENSP00000428945

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000704 AC: 177 AN: 251484 Hom.: 0 AF XY: 0.000824 AC XY: 112 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000957 AC: 1399 AN: 1461808 Hom.: 4 Cov.: 31 AF XY: 0.000938 AC XY: 682 AN XY: 727208

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000988

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74482

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000718

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 25 of the POP1 protein (p.Gly25Asp). This variant is present in population databases (rs61743394, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1519057). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

POP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	.;M;M
MutationTaster	Benign	0.64	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.077
Sift	Benign	0.15	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.45, 0.43
MVP		0.73
MPC		0.25
ClinPred		0.031	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs61743394; hg19: chr8-99135639;