chr16-22313625-C-T

Variant names:

• chr16-22313625-C-T
• rs2048293042
• NM_018119.4:c.370C>T

Variant summary

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

The NM_018119.4(POLR3E):​c.370C>T​(p.Leu124Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR3E NM_018119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

Genes affected

POLR3E (HGNC:30347): (RNA polymerase III subunit E) Predicted to enable DNA-directed 5'-3' RNA polymerase activity. Predicted to be involved in defense response to virus; innate immune response; and transcription, DNA-templated. Located in nucleoplasm. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018119.4. 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
	POLR3E	NM_018119.4	MANE Select	c.370C>T	p.Leu124Phe	missense	Exon 7 of 21	NP_060589.1	Q9NVU0-1
	POLR3E	NM_001258033.2		c.370C>T	p.Leu124Phe	missense	Exon 7 of 21	NP_001244962.1	Q9NVU0-4
	POLR3E	NM_001258034.2		c.262C>T	p.Leu88Phe	missense	Exon 6 of 20	NP_001244963.1	Q9NVU0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3E	ENST00000299853.10	TSL:1 MANE Select	c.370C>T	p.Leu124Phe	missense	Exon 7 of 21	ENSP00000299853.5	Q9NVU0-1
	POLR3E	ENST00000359210.8	TSL:1	c.370C>T	p.Leu124Phe	missense	Exon 7 of 20	ENSP00000352140.4	Q9NVU0-2
	POLR3E	ENST00000564061.5	TSL:1	n.491C>T		non_coding_transcript_exon	Exon 7 of 18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456278 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724808

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106974

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.027	D
Sift4G	Benign	0.067	T
Polyphen		0.52	P
Vest4		0.85
MutPred		0.65		Loss of sheet (P = 0.003)
MVP		0.68
MPC		0.61
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.81
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2048293042; hg19: chr16-22324946;