dbSNP rs748937304: POLR3F:p.Thr70Lys (chr20-18472870-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006466.4(POLR3F):c.209C>A(p.Thr70Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T70M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

POLR3F
NM_006466.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69

Publications

0 publications found

Variant links:

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)

POLR3F links:

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ACMG classification

Classification was made for transcript

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=0.1134198).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR3F	NM_006466.4	MANE Select	c.209C>A	p.Thr70Lys	missense	Exon 3 of 9	NP_006457.2
POLR3F	NM_001282526.2		c.86C>A	p.Thr29Lys	missense	Exon 3 of 9	NP_001269455.1	Q05DB8
POLR3F	NM_001410821.1		c.209C>A	p.Thr70Lys	missense	Exon 3 of 8	NP_001397750.1	A0A8V8TMS0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR3F	ENST00000377603.5	TSL:1 MANE Select	c.209C>A	p.Thr70Lys	missense	Exon 3 of 9	ENSP00000366828.4	Q9H1D9
POLR3F	ENST00000462997.6	TSL:1	c.86C>A	p.Thr29Lys	missense	Exon 3 of 9	ENSP00000513375.1	Q05DB8
POLR3F	ENST00000697647.1		c.209C>A	p.Thr70Lys	missense	Exon 3 of 10	ENSP00000513371.1	A0A8V8TLI4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000431

AC:

AN:

231782

AF XY:

0.00000793

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000617

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1357226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679078

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30546

American (AMR)

AF:

0.00

AC:

AN:

40358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24852

East Asian (EAS)

AF:

0.00

AC:

AN:

37252

South Asian (SAS)

AF:

0.00

AC:

AN:

78982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

9.70e-7

AC:

AN:

1031400

Other (OTH)

AF:

0.00

AC:

AN:

56156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.018

Eigen

Benign

-0.17

Eigen_PC

Benign

0.085

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.0017

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.43

PhyloP100

2.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.36

REVEL

Benign

0.036

Sift

Benign

0.78

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.29

MutPred

0.38

Gain of MoRF binding (P = 0.0251)

MVP

0.57

MPC

0.77

ClinPred

0.19

GERP RS

5.9

Varity_R

0.15

gMVP

0.35

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over