19-1090804-A-G

Variant names:

• chr19-1090804-A-G
• rs3787016
• NM_002695.5:c.429+104T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002695.5(POLR2E):​c.429+104T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 972,496 control chromosomes in the GnomAD database, including 275,264 homozygotes. 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: 𝑓 0.77 (45630 hom., cov: 32)
  • Exomes 𝑓: 0.74 (229634 hom.)
• Consequence: POLR2E NM_002695.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.24
• Publications: 62 publications found

Genes affected

POLR2E (HGNC:9192): (RNA polymerase II, I and III subunit E) This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002695.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2E	NM_002695.5	MANE Select	c.429+104T>C		intron	N/A	NP_002686.3
	POLR2E	NM_001316323.2		c.150+104T>C		intron	N/A	NP_001303252.1	B4DJ89
	POLR2E	NM_001316324.2		c.150+104T>C		intron	N/A	NP_001303253.1	B4DJ89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2E	ENST00000615234.5	TSL:1 MANE Select	c.429+104T>C		intron	N/A	ENSP00000478303.1	P19388
	POLR2E	ENST00000885900.1		c.639+104T>C		intron	N/A	ENSP00000555959.1
	POLR2E	ENST00000885899.1		c.576+104T>C		intron	N/A	ENSP00000555958.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 117092 AN: 151974 Hom.: 45591 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.752

GnomAD4 exome AF: 0.744 AC: 610676 AN: 820404 Hom.: 229634 AF XY: 0.744 AC XY: 312426 AN XY: 419908

African (AFR) AF: 0.862 AC: 17540 AN: 20340

American (AMR) AF: 0.841 AC: 25535 AN: 30378

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 13199 AN: 18354

East Asian (EAS) AF: 0.482 AC: 16162 AN: 33518

South Asian (SAS) AF: 0.733 AC: 45284 AN: 61748

European-Finnish (FIN) AF: 0.728 AC: 24168 AN: 33182

Middle Eastern (MID) AF: 0.792 AC: 3526 AN: 4452

European-Non Finnish (NFE) AF: 0.753 AC: 436447 AN: 579724

Other (OTH) AF: 0.744 AC: 28815 AN: 38708

GnomAD4 genome AF: 0.770 AC: 117179 AN: 152092 Hom.: 45630 Cov.: 32 AF XY: 0.767 AC XY: 57002 AN XY: 74348

African (AFR) AF: 0.857 AC: 35566 AN: 41504

American (AMR) AF: 0.795 AC: 12143 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2511 AN: 3472

East Asian (EAS) AF: 0.530 AC: 2737 AN: 5162

South Asian (SAS) AF: 0.700 AC: 3382 AN: 4830

European-Finnish (FIN) AF: 0.734 AC: 7769 AN: 10580

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50809 AN: 67952

Other (OTH) AF: 0.744 AC: 1571 AN: 2112

Alfa AF: 0.757 Hom.: 32069

Bravo AF: 0.779

Asia WGS AF: 0.624 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.14
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3787016; hg19: chr19-1090803; COSMIC: COSV53123968; COSMIC: COSV53123968;