Variant 9-37500845-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022490.4(POLR1E):c.892C>G(p.Leu298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLR1E
NM_022490.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0410

Variant links:

Genes affected

POLR1E (HGNC:17631): (RNA polymerase I subunit E) Predicted to enable DNA binding activity; DNA-directed 5'-3' RNA polymerase activity; and RNA polymerase I general transcription initiation factor binding activity. Involved in nucleolar large rRNA transcription by RNA polymerase I. Located in fibrillar center and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

POLR1E links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11078569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4 linkuse as main transcript	c.892C>G	p.Leu298Val	missense_variant	10/12	ENST00000377798.9	NP_071935.1	Q9GZS1-2
POLR1E	NM_001282766.2 linkuse as main transcript	c.682C>G	p.Leu228Val	missense_variant	11/13		NP_001269695.1	Q9GZS1B4E005
POLR1E	XM_047423729.1 linkuse as main transcript	c.1078C>G	p.Leu360Val	missense_variant	9/11		XP_047279685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POLR1E	ENST00000377798.9 linkuse as main transcript	c.892C>G	p.Leu298Val	missense_variant	10/12	1	NM_022490.4	ENSP00000367029.4	Q9GZS1-2
POLR1E	ENST00000377792.3 linkuse as main transcript	c.1078C>G	p.Leu360Val	missense_variant	9/11	2		ENSP00000367023.3	Q9GZS1-1
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*560C>G		non_coding_transcript_exon_variant	11/13	2		ENSP00000399887.3	E7EX70
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*560C>G		3_prime_UTR_variant	11/13	2		ENSP00000399887.3	E7EX70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251320

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.892C>G (p.L298V) alteration is located in exon 10 (coding exon 10) of the POLR1E gene. This alteration results from a C to G substitution at nucleotide position 892, causing the leucine (L) at amino acid position 298 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.051

Sift

Benign

0.052

T;T

Sift4G

Benign

0.093

T;T

Vest4

0.094

MutPred

0.58

.;Loss of stability (P = 0.0262);

MVP

0.35

MPC

0.45

ClinPred

0.26

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over