Variant 9-37501732-G-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.988G>T(p.Asp330Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,609,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

POLR1E
NM_022490.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.87

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=0.26378584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4 linkuse as main transcript	c.988G>T	p.Asp330Tyr	missense_variant	11/12	ENST00000377798.9	NP_071935.1	Q9GZS1-2
POLR1E	NM_001282766.2 linkuse as main transcript	c.778G>T	p.Asp260Tyr	missense_variant	12/13		NP_001269695.1	Q9GZS1B4E005
POLR1E	XM_047423729.1 linkuse as main transcript	c.1174G>T	p.Asp392Tyr	missense_variant	10/11		XP_047279685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POLR1E	ENST00000377798.9 linkuse as main transcript	c.988G>T	p.Asp330Tyr	missense_variant	11/12	1	NM_022490.4	ENSP00000367029.4	Q9GZS1-2
POLR1E	ENST00000377792.3 linkuse as main transcript	c.1174G>T	p.Asp392Tyr	missense_variant	10/11	2		ENSP00000367023.3	Q9GZS1-1
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*656G>T		non_coding_transcript_exon_variant	12/13	2		ENSP00000399887.3	E7EX70
POLR1E	ENST00000442009.6 linkuse as main transcript	n.*656G>T		3_prime_UTR_variant	12/13	2		ENSP00000399887.3	E7EX70

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000528

AC:

AN:

245998

Hom.:

AF XY:

0.0000527

AC XY:

AN XY:

132720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000236

AC:

344

AN:

1456850

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

162

AN XY:

724388

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.000113

Gnomad4 NFE exome

AF:

0.000298

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

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

Dec 13, 2022

The c.988G>T (p.D330Y) alteration is located in exon 11 (coding exon 11) of the POLR1E gene. This alteration results from a G to T substitution at nucleotide position 988, causing the aspartic acid (D) at amino acid position 330 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

0.21

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0083

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.057

Sift

Benign

0.044

D;D

Sift4G

Benign

0.095

T;T

Vest4

0.38

MVP

0.49

MPC

0.36

ClinPred

0.37

GERP RS

3.9

Varity_R

0.14

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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