rs8071847

Variant names:

• chr17-7504008-A-G
• rs8071847
• ENST00000674977.2:c.3240+217A>G

Variant summary

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

The ENST00000674977.2(POLR2A):​c.3240+217A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 353,180 control chromosomes in the GnomAD database, including 7,716 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 0.19 (2973 hom., cov: 31)
  • Exomes 𝑓: 0.21 (4743 hom.)
• Consequence: POLR2A ENST00000674977.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 16 publications found

Genes affected

POLR2A (HGNC:9187): (RNA polymerase II subunit A) This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

POLR2A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.3240+217A>G		intron_variant	Intron 19 of 29		NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000674977.2	c.3240+217A>G		intron_variant	Intron 19 of 29			ENSP00000502190.2
POLR2A	ENST00000617998.6	n.3639+217A>G		intron_variant	Intron 19 of 28	1
POLR2A	ENST00000574158.1	n.*52A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29128 AN: 151916 Hom.: 2977 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.207 AC: 41640 AN: 201146 Hom.: 4743 AF XY: 0.214 AC XY: 23625 AN XY: 110448

African (AFR) AF: 0.196 AC: 1020 AN: 5212

American (AMR) AF: 0.125 AC: 1312 AN: 10534

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 968 AN: 4460

East Asian (EAS) AF: 0.0322 AC: 265 AN: 8220

South Asian (SAS) AF: 0.271 AC: 11278 AN: 41686

European-Finnish (FIN) AF: 0.164 AC: 1567 AN: 9580

Middle Eastern (MID) AF: 0.272 AC: 182 AN: 668

European-Non Finnish (NFE) AF: 0.206 AC: 22967 AN: 111244

Other (OTH) AF: 0.218 AC: 2081 AN: 9542

GnomAD4 genome AF: 0.192 AC: 29129 AN: 152034 Hom.: 2973 Cov.: 31 AF XY: 0.188 AC XY: 13977 AN XY: 74328

African (AFR) AF: 0.198 AC: 8218 AN: 41456

American (AMR) AF: 0.152 AC: 2318 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 771 AN: 3468

East Asian (EAS) AF: 0.0278 AC: 144 AN: 5174

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4820

European-Finnish (FIN) AF: 0.140 AC: 1478 AN: 10582

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14081 AN: 67972

Other (OTH) AF: 0.208 AC: 440 AN: 2112

Alfa AF: 0.205 Hom.: 14011

Bravo AF: 0.193

Asia WGS AF: 0.136 AC: 476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.35
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8071847; hg19: chr17-7407327; COSMIC: COSV107378297;