9-37489353-T-C

Position:

• chr9-37489353-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022490.4(POLR1E):​c.296T>C​(p.Met99Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR1E NM_022490.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1E	NM_022490.4	c.296T>C	p.Met99Thr	missense_variant	4/12	ENST00000377798.9	NP_071935.1
POLR1E	XM_047423729.1	c.482T>C	p.Met161Thr	missense_variant	3/11		XP_047279685.1
POLR1E	NM_001282766.2	c.-9T>C		5_prime_UTR_variant	4/13		NP_001269695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1E	ENST00000377798.9	c.296T>C	p.Met99Thr	missense_variant	4/12	1	NM_022490.4	ENSP00000367029.4
POLR1E	ENST00000377792.3	c.482T>C	p.Met161Thr	missense_variant	3/11	2		ENSP00000367023.3
POLR1E	ENST00000442009.6	n.296T>C		non_coding_transcript_exon_variant	4/13	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

Dec 14, 2021

The c.296T>C (p.M99T) alteration is located in exon 4 (coding exon 4) of the POLR1E gene. This alteration results from a T to C substitution at nucleotide position 296, causing the methionine (M) at amino acid position 99 to be replaced by a threonine (T). 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	0.96
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.84
MutPred		0.86		.;Gain of catalytic residue at M161 (P = 0.0347);
MVP		0.47
MPC		0.43
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.67
gMVP		0.72

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: chr9-37489350;