chr8-22245511-C-A

Variant names:

• chr8-22245511-C-A
• rs576107129
• NM_001722.3:c.62C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001722.3(POLR3D):​c.62C>A​(p.Thr21Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,288,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. T21I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: POLR3D NM_001722.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07556662).

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.62C>A	p.Thr21Asn	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.62C>A	p.Thr21Asn	missense	Exon 2 of 9	ENSP00000303088.4	P05423
	POLR3D	ENST00000397802.8	TSL:1	c.62C>A	p.Thr21Asn	missense	Exon 1 of 8	ENSP00000380904.3	P05423
	POLR3D	ENST00000861620.1		c.62C>A	p.Thr21Asn	missense	Exon 2 of 9	ENSP00000531679.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000264 AC: 3 AN: 1136464 Hom.: 0 Cov.: 30 AF XY: 0.00000185 AC XY: 1 AN XY: 541468

African (AFR) AF: 0.00 AC: 0 AN: 24494

American (AMR) AF: 0.00 AC: 0 AN: 14532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14810

East Asian (EAS) AF: 0.00 AC: 0 AN: 29556

South Asian (SAS) AF: 0.00 AC: 0 AN: 23922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3866

European-Non Finnish (NFE) AF: 0.00000318 AC: 3 AN: 942546

Other (OTH) AF: 0.00 AC: 0 AN: 45272

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.067
Sift	Benign	0.17	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.11		Loss of phosphorylation at T21 (P = 0.007)
MVP		0.18
MPC		0.26
ClinPred		0.23	T
GERP RS		5.6
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.22
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs576107129; hg19: chr8-22103024;