rs138249161

Variant names:

• chr12-106432421-T-A
• rs138249161
• NM_018082.6:c.1568T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP2 PP3 PP5_Very_Strong

The NM_018082.6(POLR3B):​c.1568T>A​(p.Val523Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:2
• Conservation: PhyloP100: 7.64
• Publications: 33 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):

• POLR3B-related disorder

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

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 POLR3B-related disorder, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, neurodevelopmental disorder, endosteal sclerosis-cerebellar hypoplasia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 12-106432421-T-A is Pathogenic according to our data. Variant chr12-106432421-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1568T>A	p.Val523Glu	missense	Exon 15 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.1394T>A	p.Val465Glu	missense	Exon 15 of 28	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.1568T>A	p.Val523Glu	missense	Exon 15 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000970165.1		c.1568T>A	p.Val523Glu	missense	Exon 15 of 29	ENSP00000640224.1
	POLR3B	ENST00000887559.1		c.1568T>A	p.Val523Glu	missense	Exon 15 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000271 AC: 68 AN: 251090 AF XY: 0.000258

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000431 AC: 630 AN: 1461070 Hom.: 0 Cov.: 30 AF XY: 0.000392 AC XY: 285 AN XY: 726902

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000548 AC: 609 AN: 1111308

Other (OTH) AF: 0.000182 AC: 11 AN: 60368

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74452

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68010

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (13)
9	-	-	not provided (9)
2	-	-	Charcot-Marie-Tooth disease, demyelinating, IIA 1I (2)
2	-	-	POLR-related leukodystrophy (2)
1	-	-	Hypogonadotropic hypogonadism 7 with or without anosmia;C3280644:Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;CN034185:Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (1)
1	-	-	not specified (1)
1	-	-	POLR3B-related disorder (1)
1	-	-	See cases (1)
-	-	-	Hypogonadotropic hypogonadism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.69	P
Vest4		0.96
MVP		0.80
MPC		1.3
ClinPred		0.82	D
GERP RS		6.1
Varity_R		0.86
gMVP		0.94
Mutation Taster		=12/88	disease causing (ClinVar)

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

dbSNP: rs138249161; hg19: chr12-106826199;