16-22313625-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 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.370C>T	p.Leu124Phe	missense_variant	Exon 7 of 21	ENST00000299853.10	NP_060589.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3E	ENST00000299853.10	c.370C>T	p.Leu124Phe	missense_variant	Exon 7 of 21	1	NM_018119.4	ENSP00000299853.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370C>T (p.L124F) alteration is located in exon 7 (coding exon 6) of the POLR3E gene. This alteration results from a C to T substitution at nucleotide position 370, causing the leucine (L) at amino acid position 124 to be replaced by a phenylalanine (F). 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	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;T;.;.;.;.;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;D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	.;M;M;.;.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	.;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.027	.;D;D;D;D;D;T
Sift4G	Benign	0.067	T;T;T;D;T;T;D
Polyphen		0.52, 0.61	.;P;.;.;.;P;.
Vest4		0.85
MutPred		0.65		.;Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2048293042; hg19: chr16-22324946;