chr12-106427197-C-T

Variant names:

• chr12-106427197-C-T
• rs201079775
• NM_018082.6:c.1102C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_018082.6(POLR3B):​c.1102C>T​(p.Leu368Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L368V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLR3B NM_018082.6 missense, splice_region
• Scores: Splicing: ADA: 0.9888
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21
• Publications: 11 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_018082.6
• PP2: Missense variant in the POLR3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.1978 (above the threshold of 3.09). Trascript score misZ: 3.4842 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, neurodevelopmental disorder, endosteal sclerosis-cerebellar hypoplasia syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1102C>T	p.Leu368Phe	missense splice_region	Exon 13 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.928C>T	p.Leu310Phe	missense splice_region	Exon 13 of 28	NP_001154180.1	Q9NW08-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3B	ENST00000228347.9	TSL:1 MANE Select	c.1102C>T	p.Leu368Phe	missense splice_region	Exon 13 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000970165.1		c.1102C>T	p.Leu368Phe	missense splice_region	Exon 13 of 29	ENSP00000640224.1
	POLR3B	ENST00000887559.1		c.1102C>T	p.Leu368Phe	missense splice_region	Exon 13 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes AF: 0.000906 AC: 100 AN: 110352 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.000702

Gnomad EAS AF: 0.000266

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.00439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.0573 AC: 5962 AN: 103986 AF XY: 0.0606

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0271

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.0575

Gnomad OTH exome AF: 0.0385

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00573 AC: 6592 AN: 1149806 Hom.: 0 Cov.: 24 AF XY: 0.00671 AC XY: 3829 AN XY: 571052

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00373 AC: 91 AN: 24420

American (AMR) AF: 0.0252 AC: 677 AN: 26838

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 305 AN: 20264

East Asian (EAS) AF: 0.00520 AC: 173 AN: 33260

South Asian (SAS) AF: 0.0196 AC: 1221 AN: 62440

European-Finnish (FIN) AF: 0.0441 AC: 1638 AN: 37168

Middle Eastern (MID) AF: 0.0227 AC: 94 AN: 4148

European-Non Finnish (NFE) AF: 0.00247 AC: 2202 AN: 892594

Other (OTH) AF: 0.00392 AC: 191 AN: 48674

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000906 AC: 100 AN: 110402 Hom.: 0 Cov.: 28 AF XY: 0.00103 AC XY: 54 AN XY: 52470

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000461 AC: 13 AN: 28184

American (AMR) AF: 0.0000932 AC: 1 AN: 10730

Ashkenazi Jewish (ASJ) AF: 0.000702 AC: 2 AN: 2850

East Asian (EAS) AF: 0.000267 AC: 1 AN: 3744

South Asian (SAS) AF: 0.000838 AC: 3 AN: 3580

European-Finnish (FIN) AF: 0.00439 AC: 26 AN: 5928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.00100 AC: 53 AN: 52944

Other (OTH) AF: 0.000662 AC: 1 AN: 1510

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00188 Hom.: 0

ExAC AF: 0.0395 AC: 4681

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0057	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		0.43	B
Vest4		0.33
MPC		1.3
ClinPred		0.053	T
GERP RS		5.6
Varity_R		0.56
gMVP		0.86
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.030		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: rs201079775; hg19: chr12-106820975; COSMIC: COSV57275637;