12-106357893-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS1

The NM_018082.6(POLR3B):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

POLR3B
NM_018082.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.559

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
neurodevelopmental disorder
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P
POLR3B-related disorder
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease, demyelinating, IIA 1I
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
endosteal sclerosis-cerebellar hypoplasia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR3B links:

ENSG00000297327 (HGNC:):

ENSG00000297327 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PP2

Missense variant in the POLR3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.1978 (above the threshold of 3.09). Trascript score misZ: 3.4842 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, neurodevelopmental disorder, endosteal sclerosis-cerebellar hypoplasia syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066670477).

BP6

Variant 12-106357893-C-T is Benign according to our data. Variant chr12-106357893-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 722734.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000998 (152/152326) while in subpopulation AFR AF = 0.00349 (145/41570). AF 95% confidence interval is 0.00302. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018082.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3B	NM_018082.6	MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.-432C>T		upstream_gene	N/A	NP_001154180.1	Q9NW08-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR3B	ENST00000228347.9	TSL:1 MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 28	ENSP00000228347.4	Q9NW08-1
POLR3B	ENST00000970165.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 29	ENSP00000640224.1
POLR3B	ENST00000887559.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000285

AC:

AN:

249456

AF XY:

0.000200

show subpopulations

Gnomad AFR exome

AF:

0.00380

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.000116

AC:

170

AN:

1461316

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.00400

AC:

134

AN:

33472

American (AMR)

AF:

0.000291

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111934

Other (OTH)

AF:

0.000298

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152326

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00349

AC:

145

AN:

41570

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

POLR3B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.73

M_CAP

Benign

0.037

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.56

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.51

REVEL

Benign

0.090

Sift

Benign

0.24

Sift4G

Benign

0.46

Polyphen

0.32

Vest4

0.17

MVP

0.59

MPC

0.61

ClinPred

0.048

GERP RS

3.3

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.037

gMVP

0.36

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over