Genetic Variant POLR3K:p.Arg36His (chr16-53480-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_016310.5(POLR3K):c.107G>A(p.Arg36His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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. R36P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLR3K
NM_016310.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.64

Publications

0 publications found

Variant links:

Genes affected

POLR3K (HGNC:14121): (RNA polymerase III subunit K) This gene encodes a small essential subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The carboxy-terminal domain of this subunit shares a high degree of sequence similarity to the carboxy-terminal domain of an RNA polymerase II elongation factor. This similarity in sequence is supported by functional studies showing that this subunit is required for proper pausing and termination during transcription. Pseudogenes of this gene are found on chromosomes 13 and 17.[provided by RefSeq, Jul 2010]

POLR3K Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 21
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

POLR3K links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.088583 (below the threshold of 3.09). Trascript score misZ: 0.18956 (below the threshold of 3.09). GenCC associations: The gene is linked to leukodystrophy, hypomyelinating, 21.

BP4

Computational evidence support a benign effect (MetaRNN=0.1723051).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016310.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3K	NM_016310.5	MANE Select	c.107G>A	p.Arg36His	missense	Exon 1 of 3	NP_057394.3	Q9Y2Y1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3K	ENST00000293860.6	TSL:1 MANE Select	c.107G>A	p.Arg36His	missense	Exon 1 of 3	ENSP00000293860.5	Q9Y2Y1
	POLR3K	ENST00000913642.1		c.107G>A	p.Arg36His	missense	Exon 1 of 2	ENSP00000583701.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724570

African (AFR)

AF:

0.00

AC:

AN:

33236

American (AMR)

AF:

0.00

AC:

AN:

44092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

39298

South Asian (SAS)

AF:

0.00

AC:

AN:

85848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109778

Other (OTH)

AF:

0.00

AC:

AN:

60148

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.16

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.077

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

PhyloP100

5.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

REVEL

Benign

0.062

Sift

Benign

0.12

Sift4G

Benign

0.29

Vest4

0.33

MutPred

0.39

Loss of MoRF binding (P = 0.0146)

MVP

0.42

MPC

0.49

ClinPred

0.73

GERP RS

4.1

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.46

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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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