12-106427197-C-T

Position:

• chr12-106427197-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. 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 (★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR3B. . Gene score misZ 3.1978 (greater than the threshold 3.09). Trascript score misZ 3.4842 (greater than threshold 3.09). GenCC has associacion of gene with hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, endosteal sclerosis-cerebellar hypoplasia syndrome.
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, Eigen, MutationAssessor, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1102C>T	p.Leu368Phe	missense_variant, splice_region_variant	13/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.928C>T	p.Leu310Phe	missense_variant, splice_region_variant	13/28		NP_001154180.1
POLR3B	XM_017019621.3	c.1102C>T	p.Leu368Phe	missense_variant, splice_region_variant	13/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1102C>T	p.Leu368Phe	missense_variant, splice_region_variant	13/28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.928C>T	p.Leu310Phe	missense_variant, splice_region_variant	13/28	2		ENSP00000445721.1
POLR3B	ENST00000549569.1	c.376C>T	p.Leu126Phe	missense_variant, splice_region_variant	5/5	4		ENSP00000448398.1
POLR3B	ENST00000549195.1	n.512C>T		splice_region_variant, non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 100 AN: 110352 Hom.: 0 Cov.: 28 FAILED QC

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

GnomAD3 exomes AF: 0.0573 AC: 5962 AN: 103986 Hom.: 0 AF XY: 0.0606 AC XY: 3357 AN XY: 55438

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 SAS exome AF: 0.0668

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

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00520

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00392

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

Gnomad4 AFR AF: 0.000461

Gnomad4 AMR AF: 0.0000932

Gnomad4 ASJ AF: 0.000702

Gnomad4 EAS AF: 0.000267

Gnomad4 SAS AF: 0.000838

Gnomad4 FIN AF: 0.00439

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000662

Alfa AF: 0.00188 Hom.: 0

ExAC AF: 0.0395 AC: 4681

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.012	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs201079775; hg19: chr12-106820975; COSMIC: COSV57275637;