chr16-22315185-C-T

Variant names:

• chr16-22315185-C-T
• NM_018119.4:c.619C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018119.4(POLR3E):​c.619C>T​(p.His207Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,498 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: 6.9e-7 (0 hom.)
• Consequence: POLR3E NM_018119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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.619C>T	p.His207Tyr	missense	Exon 9 of 21	NP_060589.1	Q9NVU0-1
	POLR3E	NM_001258033.2		c.619C>T	p.His207Tyr	missense	Exon 9 of 21	NP_001244962.1	Q9NVU0-4
	POLR3E	NM_001258034.2		c.511C>T	p.His171Tyr	missense	Exon 8 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.619C>T	p.His207Tyr	missense	Exon 9 of 21	ENSP00000299853.5	Q9NVU0-1
	POLR3E	ENST00000359210.8	TSL:1	c.619C>T	p.His207Tyr	missense	Exon 9 of 20	ENSP00000352140.4	Q9NVU0-2
	POLR3E	ENST00000564061.5	TSL:1	n.740C>T		non_coding_transcript_exon	Exon 9 of 18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447498 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718878

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 42378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.00 AC: 0 AN: 84018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105116

Other (OTH) AF: 0.00 AC: 0 AN: 59816

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	0.15
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.035	D
Polyphen		0.20	B
Vest4		0.82
MutPred		0.71		Loss of helix (P = 0.0093)
MVP		0.65
MPC		0.48
ClinPred		0.96	D
GERP RS		5.5
PromoterAI		0.067	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.37
gMVP		0.33
Mutation Taster		=57/43	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

hg19: chr16-22326506;