9-37492659-G-A

Position:

chr9-37492659-G-A

Variant summary

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

The NM_022490.4(POLR1E):c.346G>A(p.Val116Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

POLR1E
NM_022490.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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:

Genome browser will be placed here

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=0.07991961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4 linkuse as main transcript	c.346G>A	p.Val116Ile	missense_variant, splice_region_variant	5/12	ENST00000377798.9	NP_071935.1	Q9GZS1-2
POLR1E	NM_001282766.2 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant, splice_region_variant	6/13		NP_001269695.1	Q9GZS1B4E005
POLR1E	XM_047423729.1 linkuse as main transcript	c.532G>A	p.Val178Ile	missense_variant, splice_region_variant	4/11		XP_047279685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POLR1E	ENST00000377798.9 linkuse as main transcript	c.346G>A	p.Val116Ile	missense_variant, splice_region_variant	5/12	1	NM_022490.4	ENSP00000367029.4	Q9GZS1-2
POLR1E	ENST00000377792.3 linkuse as main transcript	c.532G>A	p.Val178Ile	missense_variant, splice_region_variant	4/11	2		ENSP00000367023.3	Q9GZS1-1
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*14G>A		splice_region_variant, non_coding_transcript_exon_variant	6/13	2		ENSP00000399887.3	E7EX70
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*14G>A		3_prime_UTR_variant	6/13	2		ENSP00000399887.3	E7EX70

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251130

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000290

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:

0.00000274

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

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

Oct 12, 2022

The c.346G>A (p.V116I) alteration is located in exon 5 (coding exon 5) of the POLR1E gene. This alteration results from a G to A substitution at nucleotide position 346, causing the valine (V) at amino acid position 116 to be replaced by an isoleucine (I). 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

0.080

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.35

T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.48

N;N

REVEL

Benign

0.038

Sift

Benign

0.14

T;T

Sift4G

Benign

0.18

T;T

Vest4

0.11

MutPred

0.22

.;Loss of disorder (P = 0.154);

MVP

0.38

MPC

0.10

ClinPred

0.095

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

gMVP

0.073

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