12-106357949-G-C

Position:

chr12-106357949-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_018082.6(POLR3B):c.70G>C(p.Glu24Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000118 in 1,612,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

POLR3B
NM_018082.6 missense, splice_region

Scores

Splicing: ADA: 0.01777

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.13

Variant links:

Genes affected

POLR3B (HGNC:30348): (RNA polymerase III subunit B) This gene encodes the second largest subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The largest subunit and the encoded protein form the catalytic center of RNA polymerase III. Mutations in this gene are a cause of hypomyelinating leukodystrophy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

POLR3B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant where missense usually causes diseases, POLR3B

BP4

Computational evidence support a benign effect (MetaRNN=0.09301588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR3B	NM_018082.6 linkuse as main transcript	c.70G>C	p.Glu24Gln	missense_variant, splice_region_variant	1/28	ENST00000228347.9
POLR3B	XM_017019621.3 linkuse as main transcript	c.70G>C	p.Glu24Gln	missense_variant, splice_region_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR3B	ENST00000228347.9 linkuse as main transcript	c.70G>C	p.Glu24Gln	missense_variant, splice_region_variant	1/28	1	NM_018082.6	P1	Q9NW08-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000161

AC:

AN:

248396

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

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:

0.0000123

AC:

AN:

1460404

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 23, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 24 of the POLR3B protein (p.Glu24Gln). This variant is present in population databases (rs759363091, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLR3B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1952840). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.018

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

REVEL

Benign

0.23

Sift

Benign

0.37

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.087

MutPred

0.39

Loss of ubiquitination at K26 (P = 0.0487);

MVP

0.67

MPC

0.60

ClinPred

0.28

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.018

dbscSNV1_RF

Benign

0.25

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over