20-18472909-G-A

Variant names:

• chr20-18472909-G-A
• rs2059761164
• NM_006466.4:c.248G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006466.4(POLR3F):​c.248G>A​(p.Gly83Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000091 in 1,208,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: POLR3F NM_006466.4 missense, splice_region
• Scores: Splicing: ADA: 0.8856
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 0 publications found

Genes affected

POLR3F (HGNC:15763): (RNA polymerase III subunit F) The protein encoded by this gene is one of more than a dozen subunits forming eukaryotic RNA polymerase III (RNA Pol III), which transcribes 5S ribosomal RNA and tRNA genes. This protein has been shown to bind both TFIIIB90 and TBP, two subunits of RNA polymerase III transcription initiation factor IIIB (TFIIIB). Unlike most of the other RNA Pol III subunits, the encoded protein is unique to this polymerase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

POLR3F Gene-Disease associations (from GenCC):

• immunodeficiency 101 (varicella zoster virus-specific)

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20180866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006466.4. 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
	POLR3F	NM_006466.4	MANE Select	c.248G>A	p.Gly83Asp	missense splice_region	Exon 3 of 9	NP_006457.2
	POLR3F	NM_001282526.2		c.125G>A	p.Gly42Asp	missense splice_region	Exon 3 of 9	NP_001269455.1	Q05DB8
	POLR3F	NM_001410821.1		c.248G>A	p.Gly83Asp	missense splice_region	Exon 3 of 8	NP_001397750.1	A0A8V8TMS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3F	ENST00000377603.5	TSL:1 MANE Select	c.248G>A	p.Gly83Asp	missense splice_region	Exon 3 of 9	ENSP00000366828.4	Q9H1D9
	POLR3F	ENST00000462997.6	TSL:1	c.125G>A	p.Gly42Asp	missense splice_region	Exon 3 of 9	ENSP00000513375.1	Q05DB8
	POLR3F	ENST00000697647.1		c.248G>A	p.Gly83Asp	missense splice_region	Exon 3 of 10	ENSP00000513371.1	A0A8V8TLI4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000910 AC: 11 AN: 1208888 Hom.: 0 Cov.: 15 AF XY: 0.00000817 AC XY: 5 AN XY: 611676

African (AFR) AF: 0.00 AC: 0 AN: 27510

American (AMR) AF: 0.00 AC: 0 AN: 37582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23402

East Asian (EAS) AF: 0.00 AC: 0 AN: 36838

South Asian (SAS) AF: 0.00 AC: 0 AN: 74002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5030

European-Non Finnish (NFE) AF: 0.0000122 AC: 11 AN: 901532

Other (OTH) AF: 0.00 AC: 0 AN: 51116

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0048	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Benign	0.85
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.019
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.28
Sift	Benign	0.47	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.42		Loss of MoRF binding (P = 0.0405)
MVP		0.59
MPC		0.83
ClinPred		0.82	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.32
gMVP		0.33
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.010		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: rs2059761164; hg19: chr20-18453553;