rs201079775

Positions:

• chr12-106427197-C-G
• 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>G​(p.Leu368Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000775 in 1,160,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense, splice_region
• Scores: Splicing: ADA: 0.9638
• 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]

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1102C>G	p.Leu368Val	missense_variant, splice_region_variant	13/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.928C>G	p.Leu310Val	missense_variant, splice_region_variant	13/28		NP_001154180.1
POLR3B	XM_017019621.3	c.1102C>G	p.Leu368Val	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>G	p.Leu368Val	missense_variant, splice_region_variant	13/28	1	NM_018082.6	ENSP00000228347	P1
POLR3B	ENST00000539066.5	c.928C>G	p.Leu310Val	missense_variant, splice_region_variant	13/28	2		ENSP00000445721
POLR3B	ENST00000549569.1	c.376C>G	p.Leu126Val	missense_variant, splice_region_variant	5/5	4		ENSP00000448398
POLR3B	ENST00000549195.1	n.512C>G		splice_region_variant, non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000775 AC: 9 AN: 1160648 Hom.: 0 Cov.: 24 AF XY: 0.0000104 AC XY: 6 AN XY: 577602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000781

Gnomad4 OTH exome AF: 0.0000204

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1102C>G (p.L368V) alteration is located in exon 13 (coding exon 13) of the POLR3B gene. This alteration results from a C to G substitution at nucleotide position 1102, causing the leucine (L) at amino acid position 368 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	4.0	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.17	B;.;.
Vest4		0.64
MutPred		0.89		Loss of sheet (P = 0.1907);.;.;
MVP		0.78
MPC		0.98
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.75
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

Publications

LitVar

Other links and lift over

dbSNP: rs201079775; hg19: chr12-106820975;