rs117873765

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018082.6(POLR3B):c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 1,613,422 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0094 ( 93 hom. )

Consequence

POLR3B
NM_018082.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.385

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-106357879-C-T is Benign according to our data. Variant chr12-106357879-C-T is described in ClinVar as Benign. ClinVar VariationId is 306926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00704 (1072/152328) while in subpopulation NFE AF = 0.0108 (737/68020). AF 95% confidence interval is 0.0102. There are 11 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD gene

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.-1C>T		5_prime_UTR	Exon 1 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.-446C>T		upstream_gene	N/A	NP_001154180.1	Q9NW08-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLR3B	ENST00000228347.9	TSL:1 MANE Select	c.-1C>T	5_prime_UTR	Exon 1 of 28	ENSP00000228347.4	Q9NW08-1
POLR3B	ENST00000970165.1		c.-1C>T	5_prime_UTR	Exon 1 of 29	ENSP00000640224.1
POLR3B	ENST00000887559.1		c.-1C>T	5_prime_UTR	Exon 1 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes

AF:

0.00704

AC:

1072

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.00726

AC:

1808

AN:

249002

AF XY:

0.00745

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.00796

Gnomad ASJ exome

AF:

0.00420

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00140

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00939

AC:

13717

AN:

1461094

Hom.:

Cov.:

AF XY:

0.00922

AC XY:

6699

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33472

American (AMR)

AF:

0.00823

AC:

368

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00417

AC:

109

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00266

AC:

229

AN:

86132

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53368

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.0110

AC:

12259

AN:

1111786

Other (OTH)

AF:

0.00898

AC:

542

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

752

1503

2255

3006

3758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00704

AC:

1072

AN:

152328

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

506

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

41578

American (AMR)

AF:

0.00954

AC:

146

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

737

AN:

68020

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00929

Hom.:

Bravo

AF:

0.00746

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0128

EpiControl

AF:

0.0138

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.39

PromoterAI

-0.082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=294/6

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