Variant 12-106357785-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018082.6(POLR3B):c.-95C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,274,306 control chromosomes in the GnomAD database, including 495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 64 hom., cov: 33)

Exomes 𝑓: 0.023 ( 431 hom. )

Consequence

POLR3B
NM_018082.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.209

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-106357785-C-T is Benign according to our data. Variant chr12-106357785-C-T is described in ClinVar as [Benign]. Clinvar id is 306923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3217/152350) while in subpopulation NFE AF= 0.0276 (1878/68022). AF 95% confidence interval is 0.0266. There are 64 homozygotes in gnomad4. There are 1710 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6 link	c.-95C>T		5_prime_UTR_variant	1/28	ENST00000228347.9	NP_060552.4	Q9NW08-1Q7Z3R8
POLR3B	XM_017019621.3 link	c.-95C>T		5_prime_UTR_variant	1/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347 link	c.-95C>T		5_prime_UTR_variant	1/28	1	NM_018082.6	ENSP00000228347.4		Q9NW08-1

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3217

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.0791

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0186

GnomAD4 exome

AF:

0.0228

AC:

25540

AN:

1121956

Hom.:

431

Cov.:

AF XY:

0.0222

AC XY:

12585

AN XY:

566586

show subpopulations

Gnomad4 AFR exome

AF:

0.00331

Gnomad4 AMR exome

AF:

0.00748

Gnomad4 ASJ exome

AF:

0.0211

Gnomad4 EAS exome

AF:

0.0000856

Gnomad4 SAS exome

AF:

0.00747

Gnomad4 FIN exome

AF:

0.0812

Gnomad4 NFE exome

AF:

0.0231

Gnomad4 OTH exome

AF:

0.0206

GnomAD4 genome

AF:

0.0211

AC:

3217

AN:

152350

Hom.:

Cov.:

AF XY:

0.0230

AC XY:

1710

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0791

Gnomad4 NFE

AF:

0.0276

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0293

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	- -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over