8-22245588-G-C

Variant names:

• chr8-22245588-G-C
• rs1350169377
• NM_001722.3:c.139G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001722.3(POLR3D):​c.139G>C​(p.Asp47His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,107,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: POLR3D NM_001722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3D	NM_001722.3	c.139G>C	p.Asp47His	missense_variant	Exon 2 of 9	ENST00000306433.9	NP_001713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3D	ENST00000306433.9	c.139G>C	p.Asp47His	missense_variant	Exon 2 of 9	1	NM_001722.3	ENSP00000303088.4
POLR3D	ENST00000397802.8	c.139G>C	p.Asp47His	missense_variant	Exon 1 of 8	1		ENSP00000380904.3
POLR3D	ENST00000519237.5	c.139G>C	p.Asp47His	missense_variant	Exon 2 of 6	3		ENSP00000429677.1
POLR3D	ENST00000518039.1	n.139G>C		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000429821.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000244 AC: 27 AN: 1107914 Hom.: 0 Cov.: 31 AF XY: 0.0000267 AC XY: 14 AN XY: 524626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000194

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139G>C (p.D47H) alteration is located in exon 2 (coding exon 1) of the POLR3D gene. This alteration results from a G to C substitution at nucleotide position 139, causing the aspartic acid (D) at amino acid position 47 to be replaced by a histidine (H). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.96
MutPred		0.34		Gain of MoRF binding (P = 0.0471);Gain of MoRF binding (P = 0.0471);Gain of MoRF binding (P = 0.0471);
MVP		0.74
MPC		0.91
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs1350169377; hg19: chr8-22103101;