12-106357785-C-T

Variant names:

• chr12-106357785-C-T
• rs17219334
• NM_018082.6:c.-95C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.209
• Publications: 2 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):

• hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P
• POLR3B-related disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• 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

ENSG00000297327 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AR,AD gene

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.-95C>T		5_prime_UTR	Exon 1 of 28	NP_060552.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3B	ENST00000228347.9	TSL:1 MANE Select	c.-95C>T		5_prime_UTR	Exon 1 of 28	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000887556.1		c.-95C>T		5_prime_UTR	Exon 1 of 28	ENSP00000557615.1
	POLR3B	ENST00000887558.1		c.-95C>T		5_prime_UTR	Exon 1 of 28	ENSP00000557617.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3217 AN: 152232 Hom.: 64 Cov.: 33

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.: 16 AF XY: 0.0222 AC XY: 12585 AN XY: 566586

African (AFR) AF: 0.00331 AC: 89 AN: 26864

American (AMR) AF: 0.00748 AC: 266 AN: 35546

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 495 AN: 23424

East Asian (EAS) AF: 0.0000856 AC: 3 AN: 35038

South Asian (SAS) AF: 0.00747 AC: 551 AN: 73780

European-Finnish (FIN) AF: 0.0812 AC: 3854 AN: 47484

Middle Eastern (MID) AF: 0.0340 AC: 134 AN: 3946

European-Non Finnish (NFE) AF: 0.0231 AC: 19144 AN: 827168

Other (OTH) AF: 0.0206 AC: 1004 AN: 48706

GnomAD4 genome AF: 0.0211 AC: 3217 AN: 152350 Hom.: 64 Cov.: 33 AF XY: 0.0230 AC XY: 1710 AN XY: 74496

African (AFR) AF: 0.00325 AC: 135 AN: 41594

American (AMR) AF: 0.0104 AC: 159 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0791 AC: 840 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0276 AC: 1878 AN: 68022

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0293 Hom.: 18

Bravo AF: 0.0149

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		-0.21
PromoterAI		-0.12	Neutral
Mutation Taster		=300/0	polymorphism

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: rs17219334; hg19: chr12-106751563;