20-18481777-A-G

Variant names:

• chr20-18481777-A-G
• rs1055171
• NM_006466.4:c.840A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006466.4(POLR3F):​c.840A>G​(p.Thr280Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 1,613,084 control chromosomes in the GnomAD database, including 603,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52257 hom., cov: 30)
  • Exomes 𝑓: 0.87 (551655 hom.)
• Consequence: POLR3F NM_006466.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-18481777-A-G is Benign according to our data. Variant chr20-18481777-A-G is described in ClinVar as Benign. ClinVar VariationId is 1995826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3F	NM_006466.4	c.840A>G	p.Thr280Thr	synonymous_variant	Exon 8 of 9	ENST00000377603.5	NP_006457.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3F	ENST00000377603.5	c.840A>G	p.Thr280Thr	synonymous_variant	Exon 8 of 9	1	NM_006466.4	ENSP00000366828.4

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125648 AN: 151896 Hom.: 52238 Cov.: 30

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.871

Gnomad OTH AF: 0.822

GnomAD2 exomes AF: 0.842 AC: 211571 AN: 251126 AF XY: 0.851

Gnomad AFR exome AF: 0.747

Gnomad AMR exome AF: 0.738

Gnomad ASJ exome AF: 0.849

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.870

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.868 AC: 1268195 AN: 1461070 Hom.: 551655 Cov.: 39 AF XY: 0.870 AC XY: 632438 AN XY: 726892

African (AFR) AF: 0.742 AC: 24809 AN: 33442

American (AMR) AF: 0.745 AC: 33306 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 22059 AN: 26132

East Asian (EAS) AF: 0.818 AC: 32453 AN: 39690

South Asian (SAS) AF: 0.908 AC: 78285 AN: 86230

European-Finnish (FIN) AF: 0.870 AC: 46499 AN: 53418

Middle Eastern (MID) AF: 0.837 AC: 4826 AN: 5764

European-Non Finnish (NFE) AF: 0.876 AC: 973917 AN: 1111322

Other (OTH) AF: 0.862 AC: 52041 AN: 60356

GnomAD4 genome AF: 0.827 AC: 125703 AN: 152014 Hom.: 52257 Cov.: 30 AF XY: 0.827 AC XY: 61403 AN XY: 74288

African (AFR) AF: 0.751 AC: 31116 AN: 41454

American (AMR) AF: 0.783 AC: 11969 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2864 AN: 3470

East Asian (EAS) AF: 0.817 AC: 4200 AN: 5138

South Asian (SAS) AF: 0.912 AC: 4391 AN: 4816

European-Finnish (FIN) AF: 0.870 AC: 9182 AN: 10558

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.871 AC: 59237 AN: 67976

Other (OTH) AF: 0.824 AC: 1741 AN: 2112

Alfa AF: 0.849 Hom.: 87193

Bravo AF: 0.814

Asia WGS AF: 0.848 AC: 2950 AN: 3478

EpiCase AF: 0.864

EpiControl AF: 0.863

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.092
DANN	Benign	0.58
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1055171; hg19: chr20-18462421; COSMIC: COSV108166829; COSMIC: COSV108166829;