12-106357843-G-T

Position:

• chr12-106357843-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018082.6(POLR3B):​c.-37G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,601,204 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: POLR3B NM_018082.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.-37G>T		5_prime_UTR_premature_start_codon_gain_variant	1/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_018082.6	c.-37G>T		5_prime_UTR_variant	1/28	ENST00000228347.9	NP_060552.4
POLR3B	XM_017019621.3	c.-37G>T		5_prime_UTR_premature_start_codon_gain_variant	1/26		XP_016875110.1
POLR3B	XM_017019621.3	c.-37G>T		5_prime_UTR_variant	1/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347	c.-37G>T		5_prime_UTR_premature_start_codon_gain_variant	1/28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000228347	c.-37G>T		5_prime_UTR_variant	1/28	1	NM_018082.6	ENSP00000228347.4

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00103 AC: 243 AN: 235338 Hom.: 1 AF XY: 0.000988 AC XY: 126 AN XY: 127550

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000213

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000537 AC: 778 AN: 1448924 Hom.: 3 Cov.: 29 AF XY: 0.000533 AC XY: 384 AN XY: 720600

Gnomad4 AFR exome AF: 0.000990

Gnomad4 AMR exome AF: 0.000231

Gnomad4 ASJ exome AF: 0.0174

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000165

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74468

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs373418815; hg19: chr12-106751621; COSMIC: COSV57280422; COSMIC: COSV57280422;