rs138305578

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_007055.4(POLR3A):ā€‹c.3392A>Gā€‹(p.Lys1131Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

8
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 7.64
Variant links:
Genes affected
POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the POLR3A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.3065 (below the threshold of 3.09). Trascript score misZ: 3.6654 (above the threshold of 3.09). GenCC associations: The gene is linked to leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome, Wiedemann-Rautenstrauch syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, tremor-ataxia-central hypomyelination syndrome, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, odontoleukodystrophy.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLR3ANM_007055.4 linkc.3392A>G p.Lys1131Arg missense_variant Exon 26 of 31 ENST00000372371.8 NP_008986.2 O14802

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLR3AENST00000372371.8 linkc.3392A>G p.Lys1131Arg missense_variant Exon 26 of 31 1 NM_007055.4 ENSP00000361446.3 O14802

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251058
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135698
show subpopulations
Gnomad AFR exome
AF:
0.000431
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1460516
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726648
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000533
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Aug 16, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 31, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 549572). This missense change has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30323018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs138305578, gnomAD 0.03%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1131 of the POLR3A protein (p.Lys1131Arg). -

Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:1
May 01, 2018
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Leukodystrophy Uncertain:1
Jan 24, 2024
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

The p.Lys1131Arg variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 30323018, Yananoto et al. 2017), and has been identified in 0.05% (13/24956) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138305578). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This Lys1131Arg variant has also been reported in ClinVar (Variation ID#: 549572) and has been interpreted as likely pathogenic by the Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital) and as a variant of uncertain significance by Invitae. Of the 2 affected individuals, 1 was a compound heterozygote that carried a likely pathogenic variant in trans, which increases the likelihood that the p.Lys1131Arg variant is pathogenic (PMID: 30323018). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Lys1131Arg variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30323018). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, PM1_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.046
D
MetaRNN
Uncertain
0.50
T
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
0.84
L
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.24
Sift
Benign
0.17
T
Sift4G
Benign
0.17
T
Polyphen
0.72
P
Vest4
0.78
MVP
0.77
MPC
0.32
ClinPred
0.23
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138305578; hg19: chr10-79743715; API