16-51635-C-T

Position:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The ENST00000293860.6(POLR3K):​c.122G>A​(p.Arg41Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

POLR3K
ENST00000293860.6 missense

Scores

1
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39
Variant links:
Genes affected
POLR3K (HGNC:14121): (RNA polymerase III subunit K) This gene encodes a small essential subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The carboxy-terminal domain of this subunit shares a high degree of sequence similarity to the carboxy-terminal domain of an RNA polymerase II elongation factor. This similarity in sequence is supported by functional studies showing that this subunit is required for proper pausing and termination during transcription. Pseudogenes of this gene are found on chromosomes 13 and 17.[provided by RefSeq, Jul 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-51636-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1065610.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLR3KNM_016310.5 linkuse as main transcriptc.122G>A p.Arg41Gln missense_variant 2/3 ENST00000293860.6 NP_057394.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLR3KENST00000293860.6 linkuse as main transcriptc.122G>A p.Arg41Gln missense_variant 2/31 NM_016310.5 ENSP00000293860 P1
POLR3KENST00000481810.1 linkuse as main transcriptn.508G>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00000398
AC:
1
AN:
251344
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135864
show subpopulations
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461518
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727082
show subpopulations
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:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Leukodystrophy, hypomyelinating, 21 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 17, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
28
DANN
Pathogenic
1.0
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.59
D
MetaSVM
Benign
-0.80
T
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.8
D
REVEL
Benign
0.24
Sift
Uncertain
0.027
D
Sift4G
Uncertain
0.013
D
Vest4
0.64
MutPred
0.49
Loss of MoRF binding (P = 0.0236);
MVP
0.43
MPC
0.47
ClinPred
0.95
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs756414577; hg19: chr16-101635; API