12-106357879-C-T

Position:

• chr12-106357879-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.385

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR3B	NM_018082.6	c.-1C>T		5_prime_UTR_variant	1/28	ENST00000228347.9
POLR3B	XM_017019621.3	c.-1C>T		5_prime_UTR_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR3B	ENST00000228347.9	c.-1C>T		5_prime_UTR_variant	1/28	1	NM_018082.6	P1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1072 AN: 152210 Hom.: 11 Cov.: 33

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

GnomAD3 exomes AF: 0.00726 AC: 1808 AN: 249002 Hom.: 11 AF XY: 0.00745 AC XY: 1005 AN XY: 134886

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 SAS exome AF: 0.00295

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.: 93 Cov.: 31 AF XY: 0.00922 AC XY: 6699 AN XY: 726798

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00823

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00898

GnomAD4 genome AF: 0.00704 AC: 1072 AN: 152328 Hom.: 11 Cov.: 33 AF XY: 0.00679 AC XY: 506 AN XY: 74494

Gnomad4 AFR AF: 0.00228

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00855 Hom.: 3

Bravo AF: 0.00746

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLR3B: BP4, BS1, BS2 -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

LitVar

Other links and lift over

dbSNP: rs117873765; hg19: chr12-106751657;