12-106358132-GAGTGA-G

Position:

• chr12-106358132-GAGTGA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001160708.2(POLR3B):​c.-190_-186delTGAAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,480,626 control chromosomes in the GnomAD database, including 38,558 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5117 hom., cov: 25)
  • Exomes 𝑓: 0.22 (33441 hom.)
• Consequence: POLR3B NM_001160708.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13

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 -16 ACMG points.

• BP6: Variant 12-106358132-GAGTGA-G is Benign according to our data. Variant chr12-106358132-GAGTGA-G is described in ClinVar as [Benign]. Clinvar id is 1241806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.72+184_72+188delTGAAG		intron_variant		ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.-190_-186delTGAAG		5_prime_UTR_variant	1/28		NP_001154180.1
POLR3B	XM_017019621.3	c.72+184_72+188delTGAAG		intron_variant			XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.72+184_72+188delTGAAG		intron_variant		1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066	c.-190_-186delTGAAG		5_prime_UTR_variant	1/28	2		ENSP00000445721.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37460 AN: 151934 Hom.: 5106 Cov.: 25

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.220 AC: 292295 AN: 1328572 Hom.: 33441 AF XY: 0.219 AC XY: 142796 AN XY: 650556

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0561

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.247 AC: 37503 AN: 152054 Hom.: 5117 Cov.: 25 AF XY: 0.242 AC XY: 18018 AN XY: 74344

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0545

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.220

Alfa AF: 0.230 Hom.: 525

Bravo AF: 0.254

Asia WGS AF: 0.144 AC: 503 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome;C5676914:Charcot-Marie-Tooth disease, demyelinating, IIA 1I Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139244819; hg19: chr12-106751910;