rs1219044860

Variant names:

• chr16-22308190-C-T
• rs1219044860
• NM_018119.4:c.130C>T

Variant summary

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

The NM_018119.4(POLR3E):​c.130C>T​(p.His44Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLR3E NM_018119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3E	NM_018119.4	c.130C>T	p.His44Tyr	missense_variant	Exon 4 of 21	ENST00000299853.10	NP_060589.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3E	ENST00000299853.10	c.130C>T	p.His44Tyr	missense_variant	Exon 4 of 21	1	NM_018119.4	ENSP00000299853.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461544 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111720

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.130C>T (p.H44Y) alteration is located in exon 4 (coding exon 3) of the POLR3E gene. This alteration results from a C to T substitution at nucleotide position 130, causing the histidine (H) at amino acid position 44 to be replaced by a tyrosine (Y). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;.;.;T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.5	.;M;M;.;.;M;.
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.32	.;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	1.0	.;T;T;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T;T;T
Polyphen		0.19, 0.81	.;B;.;.;.;P;.
Vest4		0.81
MutPred		0.55		.;Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP		0.67
MPC		0.97
ClinPred		0.82	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.50
Mutation Taster		=55/45	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

Publications

LitVar

Other links and lift over

dbSNP: rs1219044860; hg19: chr16-22319511;