8-22245487-C-G

Variant names:

• chr8-22245487-C-G
• rs1830029518
• NM_001722.3:c.38C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001722.3(POLR3D):​c.38C>G​(p.Pro13Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000953 in 1,154,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000095 (0 hom.)
• Consequence: POLR3D NM_001722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27249593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001722.3. 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
	POLR3D	NM_001722.3	MANE Select	c.38C>G	p.Pro13Arg	missense	Exon 2 of 9	NP_001713.2	P05423

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3D	ENST00000306433.9	TSL:1 MANE Select	c.38C>G	p.Pro13Arg	missense	Exon 2 of 9	ENSP00000303088.4	P05423
	POLR3D	ENST00000397802.8	TSL:1	c.38C>G	p.Pro13Arg	missense	Exon 1 of 8	ENSP00000380904.3	P05423
	POLR3D	ENST00000861620.1		c.38C>G	p.Pro13Arg	missense	Exon 2 of 9	ENSP00000531679.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000953 AC: 11 AN: 1154160 Hom.: 0 Cov.: 30 AF XY: 0.0000127 AC XY: 7 AN XY: 552198

African (AFR) AF: 0.00 AC: 0 AN: 24778

American (AMR) AF: 0.00 AC: 0 AN: 17098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15184

East Asian (EAS) AF: 0.00 AC: 0 AN: 30302

South Asian (SAS) AF: 0.00 AC: 0 AN: 26538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3506

European-Non Finnish (NFE) AF: 0.0000116 AC: 11 AN: 951824

Other (OTH) AF: 0.00 AC: 0 AN: 45930

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.087
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.045	D
Polyphen		0.66	P
Vest4		0.41
MutPred		0.26		Gain of MoRF binding (P = 0.0053)
MVP		0.66
MPC		0.24
ClinPred		0.89	D
GERP RS		5.6
PromoterAI		-0.10	Neutral
Varity_R		0.18
gMVP		0.52
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1830029518; hg19: chr8-22103000;