12-106358097-C-T

Position:

• chr12-106358097-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018082.6(POLR3B):​c.72+146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,517,250 control chromosomes in the GnomAD database, including 35,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2973 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32206 hom.)
• Consequence: POLR3B NM_018082.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58

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=-0.77).
• BP6: Variant 12-106358097-C-T is Benign according to our data. Variant chr12-106358097-C-T is described in ClinVar as [Benign]. Clinvar id is 1276637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.72+146C>T		intron_variant		ENST00000228347.9	NP_060552.4
POLR3B	XM_017019621.3	c.72+146C>T		intron_variant			XP_016875110.1
POLR3B	NM_001160708.2	c.-228C>T		upstream_gene_variant			NP_001154180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.72+146C>T		intron_variant		1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066	c.-228C>T		5_prime_UTR_variant	1/28	2		ENSP00000445721.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29232 AN: 151948 Hom.: 2971 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.214 AC: 292133 AN: 1365186 Hom.: 32206 Cov.: 32 AF XY: 0.214 AC XY: 144055 AN XY: 672208

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0494

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.192 AC: 29242 AN: 152064 Hom.: 2973 Cov.: 33 AF XY: 0.191 AC XY: 14210 AN XY: 74340

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.0370

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.175

Alfa AF: 0.148 Hom.: 470

Bravo AF: 0.193

Asia WGS AF: 0.106 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17285274; hg19: chr12-106751875;