rs6539267

Variant names:

• chr12-106391776-T-C
• rs6539267
• NM_018082.6:c.724-1255T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018082.6(POLR3B):​c.724-1255T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,180 control chromosomes in the GnomAD database, including 4,746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4746 hom., cov: 32)
• Consequence: POLR3B NM_018082.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.724-1255T>C		intron_variant	Intron 9 of 27	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.550-1255T>C		intron_variant	Intron 9 of 27		NP_001154180.1
POLR3B	XM_017019621.3	c.724-1255T>C		intron_variant	Intron 9 of 25		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.724-1255T>C		intron_variant	Intron 9 of 27	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.550-1255T>C		intron_variant	Intron 9 of 27	2		ENSP00000445721.1
POLR3B	ENST00000549569.1	c.-3-1255T>C		intron_variant	Intron 1 of 4	4		ENSP00000448398.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34768 AN: 152062 Hom.: 4746 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.236

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34772 AN: 152180 Hom.: 4746 Cov.: 32 AF XY: 0.225 AC XY: 16757 AN XY: 74386

African (AFR) AF: 0.106 AC: 4386 AN: 41538

American (AMR) AF: 0.206 AC: 3139 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3468

East Asian (EAS) AF: 0.0414 AC: 215 AN: 5188

South Asian (SAS) AF: 0.252 AC: 1217 AN: 4824

European-Finnish (FIN) AF: 0.298 AC: 3151 AN: 10572

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20466 AN: 68008

Other (OTH) AF: 0.234 AC: 493 AN: 2110

Alfa AF: 0.266 Hom.: 12024

Bravo AF: 0.217

Asia WGS AF: 0.133 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.83
DANN	Benign	0.47
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs6539267; hg19: chr12-106785554;