Genetic Variant NM_006467.3:c.116C>T (chr5-90485683-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_006467.3(POLR3G):c.116C>T(p.Pro39Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000199 in 1,602,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. P39S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

POLR3G
NM_006467.3 missense, splice_region

Scores

Splicing: ADA: 0.9912

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62

Publications

3 publications found

Variant links:

Genes affected

POLR3G (HGNC:30075): (RNA polymerase III subunit G) Enables chromatin binding activity. Involved in positive regulation of innate immune response; positive regulation of interferon-beta production; and transcription by RNA polymerase III. Acts upstream of or within cell population proliferation. Located in cytosol and nuclear body. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

POLR3G links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR3G	NM_006467.3	MANE Select	c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	NP_006458.2	O15318
POLR3G	NM_001370351.1		c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	NP_001357280.1	O15318
POLR3G	NM_001370354.1		c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	NP_001357283.1	O15318

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR3G	ENST00000651687.1	MANE Select	c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	ENSP00000498469.1	O15318
POLR3G	ENST00000504930.5	TSL:2	c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	ENSP00000421637.1	O15318
POLR3G	ENST00000859024.1		c.116C>T	p.Pro39Leu	missense splice_region	Exon 2 of 8	ENSP00000529083.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000650

AC:

AN:

246152

AF XY:

0.0000450

show subpopulations

Gnomad AFR exome

AF:

0.0000648

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:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000214

AC:

311

AN:

1450470

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

164

AN XY:

722066

show subpopulations

African (AFR)

AF:

0.0000603

AC:

AN:

33156

American (AMR)

AF:

0.00

AC:

AN:

44152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

85346

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000276

AC:

304

AN:

1103120

Other (OTH)

AF:

0.0000667

AC:

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000150

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000828

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.6

PhyloP100

5.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-10

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.59

Loss of disorder (P = 0.0114)

MVP

0.54

MPC

0.44

ClinPred

1.0

GERP RS

5.4

Varity_R

0.88

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.050

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over