rs201079775

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-106427197-C-A
• 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>A​(p.Leu368Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000517 in 1,160,716 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense, splice_region
• Scores: Splicing: ADA: 0.9678
• Clinical Significance: Not reported in ClinVar
• 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 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 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 rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1102C>A	p.Leu368Ile	missense_variant, splice_region_variant	Exon 13 of 28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.928C>A	p.Leu310Ile	missense_variant, splice_region_variant	Exon 13 of 28		NP_001154180.1
POLR3B	XM_017019621.3	c.1102C>A	p.Leu368Ile	missense_variant, splice_region_variant	Exon 13 of 26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1102C>A	p.Leu368Ile	missense_variant, splice_region_variant	Exon 13 of 28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.928C>A	p.Leu310Ile	missense_variant, splice_region_variant	Exon 13 of 28	2		ENSP00000445721.1
POLR3B	ENST00000549569.1	c.376C>A	p.Leu126Ile	missense_variant, splice_region_variant	Exon 5 of 5	4		ENSP00000448398.1
POLR3B	ENST00000549195.1	n.512C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000517 AC: 6 AN: 1160716 Hom.: 0 Cov.: 24 AF XY: 0.00000519 AC XY: 3 AN XY: 577632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000476

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000446

Gnomad4 OTH exome AF: 0.0000204

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.48	P;.;.
Vest4		0.67
MutPred		0.88		Gain of catalytic residue at L368 (P = 0.1665);.;.;
MVP		0.79
MPC		1.2
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.54
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.80
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-106820975;