NM_018082.6:c.1244T>C

Variant names:

• chr12-106427339-T-C
• rs199504211
• NM_018082.6:c.1244T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP5 BS1_Supporting

The NM_018082.6(POLR3B):​c.1244T>C​(p.Met415Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M415K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:9 O:1
• Conservation: PhyloP100: 7.52
• Publications: 6 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: Uncertain_significance. The variant received 1 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 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.
• PP5: Variant 12-106427339-T-C is Pathogenic according to our data. Variant chr12-106427339-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285205.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000643 (98/152328) while in subpopulation NFE AF = 0.00134 (91/68032). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1244T>C	p.Met415Thr	missense	Exon 13 of 28	NP_060552.4
	POLR3B	NM_001160708.2		c.1070T>C	p.Met357Thr	missense	Exon 13 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.1244T>C	p.Met415Thr	missense	Exon 13 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000970165.1		c.1244T>C	p.Met415Thr	missense	Exon 13 of 29	ENSP00000640224.1
	POLR3B	ENST00000887559.1		c.1244T>C	p.Met415Thr	missense	Exon 13 of 28	ENSP00000557618.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000554 AC: 139 AN: 251068 AF XY: 0.000553

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000895 AC: 1308 AN: 1461464 Hom.: 1 Cov.: 32 AF XY: 0.000851 AC XY: 619 AN XY: 727058

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00114 AC: 1266 AN: 1111704

Other (OTH) AF: 0.000497 AC: 30 AN: 60374

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74494

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00158

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	3	-	not provided (7)
4	1	-	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (6)
-	1	-	Amenorrhea (1)
-	1	-	Hypogonadotropic hypogonadism 7 with or without anosmia;C3280644:Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome (1)
1	-	-	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C5676914:Charcot-Marie-Tooth disease, demyelinating, IIA 1I (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	1	-	not specified (1)
-	1	-	POLR-related leukodystrophy (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.42	B
Vest4		0.98
MVP		0.78
MPC		1.1
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.71
gMVP		0.91
Mutation Taster		=9/91	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: rs199504211; hg19: chr12-106821117; COSMIC: COSV99075432; COSMIC: COSV99075432;