chr20-18472870-C-T

Variant names:

• chr20-18472870-C-T
• rs748937304
• NM_006466.4:c.209C>T

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.209C>T​(p.Thr70Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,509,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T70S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: POLR3F NM_006466.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69
• 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=0.233102).

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.209C>T	p.Thr70Met	missense	Exon 3 of 9	NP_006457.2
	POLR3F	NM_001282526.2		c.86C>T	p.Thr29Met	missense	Exon 3 of 9	NP_001269455.1	Q05DB8
	POLR3F	NM_001410821.1		c.209C>T	p.Thr70Met	missense	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.209C>T	p.Thr70Met	missense	Exon 3 of 9	ENSP00000366828.4	Q9H1D9
	POLR3F	ENST00000462997.6	TSL:1	c.86C>T	p.Thr29Met	missense	Exon 3 of 9	ENSP00000513375.1	Q05DB8
	POLR3F	ENST00000697652.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000513376.1	A0A8V8TL53

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000345 AC: 8 AN: 231782 AF XY: 0.0000555

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000938

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 21 AN: 1357224 Hom.: 0 Cov.: 20 AF XY: 0.0000191 AC XY: 13 AN XY: 679076

African (AFR) AF: 0.00 AC: 0 AN: 30546

American (AMR) AF: 0.00 AC: 0 AN: 40358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24852

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37252

South Asian (SAS) AF: 0.0000760 AC: 6 AN: 78982

European-Finnish (FIN) AF: 0.0000957 AC: 5 AN: 52262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.00000582 AC: 6 AN: 1031400

Other (OTH) AF: 0.0000534 AC: 3 AN: 56156

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151974 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.042
Sift	Benign	0.087	T
Sift4G	Benign	0.070	T
Polyphen		0.68	P
Vest4		0.26
MutPred		0.32		Gain of MoRF binding (P = 0.0648)
MVP		0.72
MPC		1.2
ClinPred		0.14	T
GERP RS		5.9
Varity_R		0.068
gMVP		0.29
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs748937304; hg19: chr20-18453514; COSMIC: COSV101112300; COSMIC: COSV101112300;