9-37495271-A-G

Position:

• chr9-37495271-A-G

Variant summary

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

The NM_022490.4(POLR1E):​c.650A>G​(p.Glu217Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: POLR1E NM_022490.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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=0.3303403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4	c.650A>G	p.Glu217Gly	missense_variant	7/12	ENST00000377798.9	NP_071935.1
POLR1E	NM_001282766.2	c.440A>G	p.Glu147Gly	missense_variant	8/13		NP_001269695.1
POLR1E	XM_047423729.1	c.836A>G	p.Glu279Gly	missense_variant	6/11		XP_047279685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1E	ENST00000377798.9	c.650A>G	p.Glu217Gly	missense_variant	7/12	1	NM_022490.4	ENSP00000367029.4
POLR1E	ENST00000377792.3	c.836A>G	p.Glu279Gly	missense_variant	6/11	2		ENSP00000367023.3
POLR1E	ENST00000442009.6	n.*318A>G		non_coding_transcript_exon_variant	8/13	2		ENSP00000399887.3
POLR1E	ENST00000442009.6	n.*318A>G		3_prime_UTR_variant	8/13	2		ENSP00000399887.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 05, 2024

The c.650A>G (p.E217G) alteration is located in exon 7 (coding exon 7) of the POLR1E gene. This alteration results from a A to G substitution at nucleotide position 650, causing the glutamic acid (E) at amino acid position 217 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Vest4		0.21
MutPred		0.70		.;Loss of disorder (P = 0.0449);
MVP		0.49
MPC		0.17
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-37495268;