rs139244819

Variant names:

• chr12-106358132-GAGTGA-G
• rs139244819
• NM_018082.6:c.72+184_72+188delTGAAG

Your query was ambiguous. Multiple possible variants found:

• chr12-106358132-GAGTGA-G
• chr12-106358132-GAGTGA-GAGTGAAGTGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001160708.2(POLR3B):​c.-190_-186delTGAAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,480,626 control chromosomes in the GnomAD database, including 38,558 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5117 hom., cov: 25)
  • Exomes 𝑓: 0.22 (33441 hom.)
• Consequence: POLR3B NM_001160708.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• Publications: 1 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

ENSG00000297327 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-106358132-GAGTGA-G is Benign according to our data. Variant chr12-106358132-GAGTGA-G is described in ClinVar as Benign. ClinVar VariationId is 1241806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160708.2. 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.72+184_72+188delTGAAG		intron	N/A	NP_060552.4
	POLR3B	NM_001160708.2		c.-190_-186delTGAAG		5_prime_UTR	Exon 1 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.72+184_72+188delTGAAG		intron	N/A	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000539066.5	TSL:2	c.-190_-186delTGAAG		5_prime_UTR	Exon 1 of 28	ENSP00000445721.1	Q9NW08-2
	POLR3B	ENST00000970165.1		c.72+184_72+188delTGAAG		intron	N/A	ENSP00000640224.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37460 AN: 151934 Hom.: 5106 Cov.: 25

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.220 AC: 292295 AN: 1328572 Hom.: 33441 AF XY: 0.219 AC XY: 142796 AN XY: 650556

African (AFR) AF: 0.365 AC: 10932 AN: 29988

American (AMR) AF: 0.234 AC: 6857 AN: 29324

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3299 AN: 21368

East Asian (EAS) AF: 0.0561 AC: 1972 AN: 35172

South Asian (SAS) AF: 0.226 AC: 15826 AN: 69932

European-Finnish (FIN) AF: 0.175 AC: 5353 AN: 30584

Middle Eastern (MID) AF: 0.181 AC: 684 AN: 3782

European-Non Finnish (NFE) AF: 0.224 AC: 235655 AN: 1053194

Other (OTH) AF: 0.212 AC: 11717 AN: 55228

GnomAD4 genome AF: 0.247 AC: 37503 AN: 152054 Hom.: 5117 Cov.: 25 AF XY: 0.242 AC XY: 18018 AN XY: 74344

African (AFR) AF: 0.362 AC: 15002 AN: 41430

American (AMR) AF: 0.202 AC: 3087 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 512 AN: 3470

East Asian (EAS) AF: 0.0545 AC: 282 AN: 5172

South Asian (SAS) AF: 0.223 AC: 1077 AN: 4820

European-Finnish (FIN) AF: 0.185 AC: 1957 AN: 10582

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.220 AC: 14932 AN: 67978

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.230 Hom.: 525

Bravo AF: 0.254

Asia WGS AF: 0.144 AC: 503 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome;C5676914:Charcot-Marie-Tooth disease, demyelinating, IIA 1I (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139244819; hg19: chr12-106751910; COSMIC: COSV57276744;