12-106357800-G-A

Variant names:

• chr12-106357800-G-A
• rs377009599
• NM_018082.6:c.-80G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018082.6(POLR3B):​c.-80G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,390,072 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: POLR3B NM_018082.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.154
• Publications: 0 publications found

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]

POLR3B Gene-Disease associations (from GenCC):

• POLR3B-related disorder

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P
• neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P
• Charcot-Marie-Tooth disease, demyelinating, IIA 1I

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• endosteal sclerosis-cerebellar hypoplasia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297327 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-106357800-G-A is Benign according to our data. Variant chr12-106357800-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1219149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00544 (828/152282) while in subpopulation AFR AF = 0.0191 (796/41572). AF 95% confidence interval is 0.018. There are 7 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018082.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3B	NM_018082.6	MANE Select	c.-80G>A		5_prime_UTR	Exon 1 of 28	NP_060552.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3B	ENST00000228347.9	TSL:1 MANE Select	c.-80G>A		5_prime_UTR	Exon 1 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000887559.1		c.-80G>A		5_prime_UTR	Exon 1 of 28	ENSP00000557618.1
	POLR3B	ENST00000887556.1		c.-80G>A		5_prime_UTR	Exon 1 of 28	ENSP00000557615.1

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 825 AN: 152164 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000538 AC: 666 AN: 1237790 Hom.: 4 Cov.: 18 AF XY: 0.000435 AC XY: 270 AN XY: 620254

African (AFR) AF: 0.0185 AC: 543 AN: 29304

American (AMR) AF: 0.00110 AC: 40 AN: 36312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36668

South Asian (SAS) AF: 0.0000908 AC: 7 AN: 77060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49382

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4470

European-Non Finnish (NFE) AF: 0.0000194 AC: 18 AN: 927736

Other (OTH) AF: 0.00108 AC: 57 AN: 52638

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152282 Hom.: 7 Cov.: 33 AF XY: 0.00470 AC XY: 350 AN XY: 74460

African (AFR) AF: 0.0191 AC: 796 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00579

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.1
DANN	Benign	0.96
PhyloP100		-0.15
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs377009599; hg19: chr12-106751578;