Variant 9-37486055-C-T 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.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,448,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000062 ( 0 hom. )

Consequence

POLR1E
NM_022490.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.145

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=0.09646168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/12	ENST00000377798.9	NP_071935.1	Q9GZS1-2
POLR1E	NM_001282766.2 linkuse as main transcript	c.-297C>T		5_prime_UTR_variant	1/13		NP_001269695.1	Q9GZS1B4E005

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1E	ENST00000377798.9 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/12	1	NM_022490.4	ENSP00000367029.4		Q9GZS1-2
POLR1E	ENST00000442009.6 linkuse as main transcript	n.8C>T		non_coding_transcript_exon_variant	1/13	2		ENSP00000399887.3		E7EX70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000224

AC:

AN:

223500

Hom.:

AF XY:

0.0000415

AC XY:

AN XY:

120604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000602

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000393

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000621

AC:

AN:

1448120

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

718886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000331

AC:

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 21, 2024

The c.8C>T (p.A3V) alteration is located in exon 1 (coding exon 1) of the POLR1E gene. This alteration results from a C to T substitution at nucleotide position 8, causing the alanine (A) at amino acid position 3 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

0.21

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.78

M_CAP

Benign

0.023

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.64

REVEL

Benign

0.083

Sift

Uncertain

0.020

Sift4G

Benign

0.062

Vest4

0.10

MutPred

0.12

Loss of helix (P = 0.079);

MVP

0.26

MPC

0.13

ClinPred

0.77

GERP RS

3.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.4

Varity_R

0.10

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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