chr12-106496119-C-G

Variant names:

• chr12-106496119-C-G
• rs267608689
• NM_018082.6:c.2778C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_018082.6(POLR3B):​c.2778C>G​(p.Asp926Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D926G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.47
• Publications: 3 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):

• neurodevelopmental disorder

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P
• hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

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

ENSG00000257545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-106496118-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 419234.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 12-106496119-C-G is Pathogenic according to our data. Variant chr12-106496119-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31163.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.2778C>G	p.Asp926Glu	missense_variant	Exon 24 of 28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.2604C>G	p.Asp868Glu	missense_variant	Exon 24 of 28		NP_001154180.1
POLR3B	XM_017019621.3	c.2778C>G	p.Asp926Glu	missense_variant	Exon 24 of 26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.2778C>G	p.Asp926Glu	missense_variant	Exon 24 of 28	1	NM_018082.6	ENSP00000228347.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Pathogenic:1 Other:1

Nov 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		1.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.94		Gain of glycosylation at S921 (P = 0.1567);.;
MVP		0.74
MPC		1.5
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.92
gMVP		0.93
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs267608689; hg19: chr12-106889897;