12-106437679-A-G

Variant names:

• chr12-106437679-A-G
• rs267608686
• NM_018082.6:c.1857-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_018082.6(POLR3B):​c.1857-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000043 in 1,395,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: POLR3B NM_018082.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.91
• 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):

• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02910053 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of -44, new splice context is: tattatataaaatactgcAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.1857-2A>G		splice_acceptor intron	N/A	NP_060552.4
	POLR3B	NM_001160708.2		c.1683-2A>G		splice_acceptor intron	N/A	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.1857-2A>G		splice_acceptor intron	N/A	ENSP00000228347.4	Q9NW08-1
	POLR3B	ENST00000970165.1		c.1857-2A>G		splice_acceptor intron	N/A	ENSP00000640224.1
	POLR3B	ENST00000887559.1		c.1869-2A>G		splice_acceptor intron	N/A	ENSP00000557618.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249980 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1395756 Hom.: 0 Cov.: 25 AF XY: 0.00000573 AC XY: 4 AN XY: 698464

African (AFR) AF: 0.0000619 AC: 2 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000285 AC: 3 AN: 1052144

Other (OTH) AF: 0.00 AC: 0 AN: 58052

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		4.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 13
DS_AL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs267608686; hg19: chr12-106831457;