9-37503085-A-C

Position:

• chr9-37503085-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022490.4(POLR1E):​c.1143A>C​(p.Lys381Asn) 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 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR1E NM_022490.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.934

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27683127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4	c.1143A>C	p.Lys381Asn	missense_variant	12/12	ENST00000377798.9	NP_071935.1
POLR1E	NM_001282766.2	c.933A>C	p.Lys311Asn	missense_variant	13/13		NP_001269695.1
POLR1E	XM_047423729.1	c.1329A>C	p.Lys443Asn	missense_variant	11/11		XP_047279685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1E	ENST00000377798.9	c.1143A>C	p.Lys381Asn	missense_variant	12/12	1	NM_022490.4	ENSP00000367029.4
POLR1E	ENST00000377792.3	c.1329A>C	p.Lys443Asn	missense_variant	11/11	2		ENSP00000367023.3
POLR1E	ENST00000442009.6	n.*811A>C		non_coding_transcript_exon_variant	13/13	2		ENSP00000399887.3
POLR1E	ENST00000442009.6	n.*811A>C		3_prime_UTR_variant	13/13	2		ENSP00000399887.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.1143A>C (p.K381N) alteration is located in exon 12 (coding exon 12) of the POLR1E gene. This alteration results from a A to C substitution at nucleotide position 1143, causing the lysine (K) at amino acid position 381 to be replaced by an asparagine (N). 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	Pathogenic	0.66
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.45
MutPred		0.64		.;Loss of methylation at K443 (P = 0.0355);
MVP		0.40
MPC		0.26
ClinPred		0.83	D
GERP RS		2.0
Varity_R		0.23
gMVP		0.59

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

Other links and lift over

dbSNP: rs1820918286; hg19: chr9-37503082;