chr12-106432384-AT-A

Position:

• chr12-106432384-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018082.6(POLR3B):​c.1533del​(p.Ile511MetfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: POLR3B NM_018082.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.64

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-106432384-AT-A is Pathogenic according to our data. Variant chr12-106432384-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 31165.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-106432384-AT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1533del	p.Ile511MetfsTer4	frameshift_variant	15/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.1359del	p.Ile453MetfsTer4	frameshift_variant	15/28		NP_001154180.1
POLR3B	XM_017019621.3	c.1533del	p.Ile511MetfsTer4	frameshift_variant	15/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1533del	p.Ile511MetfsTer4	frameshift_variant	15/28	1	NM_018082.6	ENSP00000228347	P1
POLR3B	ENST00000539066.5	c.1359del	p.Ile453MetfsTer4	frameshift_variant	15/28	2		ENSP00000445721

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251162 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2011	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Feb 24, 2022	The p.Ile511fs variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036172) and has been identified in 0.002% (2/113510) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1006308316). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 31165) and has been interpreted as pathogenic by OMIM and GeneReviews. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 511 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs267608684; hg19: chr12-106826162;