Genetic Variant POLR3D:p.Pro34Ser (chr8-22245549-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001722.3(POLR3D):c.100C>T(p.Pro34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLR3D
NM_001722.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.123

Variant links:

Genes affected

POLR3D (HGNC:1080): (RNA polymerase III subunit D) This gene complements a temperature-sensitive mutant isolated from the BHK-21 Syrian hamster cell line. It leads to a block in progression through the G1 phase of the cell cycle at nonpermissive temperatures. [provided by RefSeq, Jul 2008]

POLR3D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04734063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3D	NM_001722.3 link	c.100C>T	p.Pro34Ser	missense_variant	Exon 2 of 9	ENST00000306433.9	NP_001713.2	P05423

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLR3D	ENST00000306433.9 link	c.100C>T	p.Pro34Ser	missense_variant	Exon 2 of 9	1	NM_001722.3	ENSP00000303088.4	P05423
POLR3D	ENST00000397802.8 link	c.100C>T	p.Pro34Ser	missense_variant	Exon 1 of 8	1		ENSP00000380904.3	P05423
POLR3D	ENST00000519237.5 link	c.100C>T	p.Pro34Ser	missense_variant	Exon 2 of 6	3		ENSP00000429677.1	E5RHT4
POLR3D	ENST00000518039.1 link	n.100C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000429821.1	E7EQ68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1110658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

526030

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100C>T (p.P34S) alteration is located in exon 2 (coding exon 1) of the POLR3D gene. This alteration results from a C to T substitution at nucleotide position 100, causing the proline (P) at amino acid position 34 to be replaced by a serine (S). 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

0.067

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.0

DANN

Benign

0.82

DEOGEN2

Benign

0.016

T;.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

L;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.55

N;N;N

REVEL

Benign

0.027

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.10

MutPred

0.28

Loss of catalytic residue at P33 (P = 0.0108);Loss of catalytic residue at P33 (P = 0.0108);Loss of catalytic residue at P33 (P = 0.0108);

MVP

0.16

MPC

0.23

ClinPred

0.065

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over