Genetic Variant POLR3G:p.Ala129Ser (chr5-90501935-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006467.3(POLR3G):c.385G>T(p.Ala129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A129T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLR3G
NM_006467.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.43

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3G	NM_006467.3 link	c.385G>T	p.Ala129Ser	missense_variant	Exon 6 of 8	ENST00000651687.1	NP_006458.2	O15318A0A024RAM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLR3G	ENST00000651687.1 link	c.385G>T	p.Ala129Ser	missense_variant	Exon 6 of 8		NM_006467.3	ENSP00000498469.1	O15318
POLR3G	ENST00000504930.5 link	c.385G>T	p.Ala129Ser	missense_variant	Exon 6 of 8	2		ENSP00000421637.1	O15318
POLR3G	ENST00000503373.5 link	c.385G>T	p.Ala129Ser	missense_variant	Exon 6 of 8	4		ENSP00000422892.1	D6R9U7
POLR3G	ENST00000399107.6 link	n.414G>T		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000382058.2	A0A7I2R591

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111590

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.033

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0017

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.51

T;T;.

M_CAP

Benign

0.0019

MetaRNN

Benign

0.033

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.40

.;N;N

PhyloP100

-1.4

PrimateAI

Benign

0.24

PROVEAN

Benign

0.27

N;N;N

REVEL

Benign

0.038

Sift

Benign

0.84

T;T;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.18

.;B;B

Vest4

0.088

MutPred

0.19

Gain of phosphorylation at A129 (P = 0.0068);Gain of phosphorylation at A129 (P = 0.0068);Gain of phosphorylation at A129 (P = 0.0068);

MVP

0.081

MPC

0.076

ClinPred

0.070

GERP RS

-3.8

Varity_R

0.025

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: -29

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

Publications

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5-90501935-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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