rs3851634

Variant names:

• chr12-106419124-T-C
• rs3851634
• NM_018082.6:c.1102-8073T>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.1102-8073T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,122 control chromosomes in the GnomAD database, including 4,373 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 0.22 (4373 hom., cov: 32)
• Consequence: POLR3B NM_018082.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670
• Publications: 5 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=-0.61).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1102-8073T>C		intron_variant	Intron 12 of 27	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.928-8073T>C		intron_variant	Intron 12 of 27		NP_001154180.1
POLR3B	XM_017019621.3	c.1102-8073T>C		intron_variant	Intron 12 of 25		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1102-8073T>C		intron_variant	Intron 12 of 27	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.928-8073T>C		intron_variant	Intron 12 of 27	2		ENSP00000445721.1
POLR3B	ENST00000549569.1	c.376-8073T>C		intron_variant	Intron 4 of 4	4		ENSP00000448398.1
POLR3B	ENST00000549195.1	n.512-8073T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33541 AN: 152004 Hom.: 4372 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.228

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

GnomAD4 genome AF: 0.221 AC: 33545 AN: 152122 Hom.: 4373 Cov.: 32 AF XY: 0.218 AC XY: 16233 AN XY: 74346

African (AFR) AF: 0.104 AC: 4323 AN: 41528

American (AMR) AF: 0.200 AC: 3056 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3472

East Asian (EAS) AF: 0.0409 AC: 212 AN: 5184

South Asian (SAS) AF: 0.254 AC: 1226 AN: 4824

European-Finnish (FIN) AF: 0.294 AC: 3101 AN: 10560

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19612 AN: 67958

Other (OTH) AF: 0.226 AC: 476 AN: 2108

Alfa AF: 0.273 Hom.: 3075

Bravo AF: 0.209

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.067
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: rs3851634; hg19: chr12-106812902;