rs755312623

Positions:

• chr12-106444495-C-G
• chr12-106444495-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_018082.6(POLR3B):​c.1988C>G​(p.Thr663Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1988C>G	p.Thr663Ser	missense_variant	19/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.1814C>G	p.Thr605Ser	missense_variant	19/28		NP_001154180.1
POLR3B	XM_017019621.3	c.1988C>G	p.Thr663Ser	missense_variant	19/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1988C>G	p.Thr663Ser	missense_variant	19/28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.1814C>G	p.Thr605Ser	missense_variant	19/28	2		ENSP00000445721.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.46
Sift	Benign	0.18	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.38	B;.
Vest4		0.73
MutPred		0.50		Loss of sheet (P = 0.0181);.;
MVP		0.68
MPC		0.71
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.56
gMVP		0.67

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-106838273;