Genetic Variant POLR3GL:p.Arg12Gln (chr1-145974900-G-A) – 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_032305.3(POLR3GL):c.35G>A(p.Arg12Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,368,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

POLR3GL
NM_032305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.57

Publications

0 publications found

Variant links:

Genes affected

POLR3GL (HGNC:28466): (RNA polymerase III subunit GL) Predicted to enable chromatin binding activity. Involved in transcription by RNA polymerase III. Located in nucleus. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

POLR3GL links:

ENSG00000280778 (HGNC:):

ENSG00000280778 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
POLR3GL	NM_032305.3 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 8	ENST00000369314.2	NP_115681.1	Q9BT43
POLR3GL	NM_001330685.2 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 7		NP_001317614.1	Q9BT43A6NGX6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3GL	ENST00000369314.2 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 8	1	NM_032305.3	ENSP00000358320.1		Q9BT43
ENSG00000280778	ENST00000625258.1 link	c.-29-2184G>A		intron_variant	Intron 1 of 3	5		ENSP00000487094.1		A0A0D9SG24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000255

AC:

AN:

156642

AF XY:

0.0000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000802

Gnomad ASJ exome

AF:

0.000154

Gnomad EAS exome

AF:

0.000108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000301

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1368428

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

676724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28008

American (AMR)

AF:

0.0000441

AC:

AN:

22688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22970

East Asian (EAS)

AF:

0.0000296

AC:

AN:

33836

South Asian (SAS)

AF:

0.0000141

AC:

AN:

71142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076022

Other (OTH)

AF:

0.0000178

AC:

AN:

56304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.35G>A (p.R12Q) alteration is located in exon 2 (coding exon 1) of the POLR3GL gene. This alteration results from a G to A substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_noAF

Pathogenic

0.66

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.095

T;T

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Uncertain

0.52

D;D

PhyloP100

8.6

PROVEAN

Benign

-2.4

N;N

Sift

Benign

0.063

T;T

Sift4G

Uncertain

0.0080

D;D

Vest4

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.56

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

Publications

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chr1-145974900-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over