chr12-106357924-G-C

Variant names:

• chr12-106357924-G-C
• NM_018082.6:c.45G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018082.6(POLR3B):​c.45G>C​(p.Gln15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 0 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):

• hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P
• POLR3B-related disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• 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

ENSG00000297327 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11484143).

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.45G>C	p.Gln15His	missense	Exon 1 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.-401G>C		upstream_gene	N/A	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.45G>C	p.Gln15His	missense	Exon 1 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000970165.1		c.45G>C	p.Gln15His	missense	Exon 1 of 29	ENSP00000640224.1
	POLR3B	ENST00000887559.1		c.45G>C	p.Gln15His	missense	Exon 1 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.18
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.24		Gain of helix (P = 0.132)
MVP		0.53
MPC		0.57
ClinPred		0.26	T
GERP RS		3.3
PromoterAI		-0.083	Neutral
Varity_R		0.088
gMVP		0.46
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr12-106751702;