rs7219550

Variant names:

• chr17-7498352-G-A
• rs7219550
• ENST00000674977.2:c.1335+142G>A

Variant summary

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

The ENST00000674977.2(POLR2A):​c.1335+142G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 868,092 control chromosomes in the GnomAD database, including 14,723 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 0.17 (2493 hom., cov: 33)
  • Exomes 𝑓: 0.18 (12230 hom.)
• Consequence: POLR2A ENST00000674977.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.1335+142G>A		intron_variant	Intron 8 of 29		NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000674977.2	c.1335+142G>A		intron_variant	Intron 8 of 29			ENSP00000502190.2
POLR2A	ENST00000572844.1	n.1480+142G>A		intron_variant	Intron 8 of 9	1
POLR2A	ENST00000617998.6	n.1734+142G>A		intron_variant	Intron 8 of 28	1
POLR2A	ENST00000576952.1	n.365G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25743 AN: 152108 Hom.: 2480 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.175 AC: 125452 AN: 715866 Hom.: 12230 Cov.: 9 AF XY: 0.176 AC XY: 64516 AN XY: 367218

African (AFR) AF: 0.107 AC: 1985 AN: 18500

American (AMR) AF: 0.229 AC: 6066 AN: 26510

Ashkenazi Jewish (ASJ) AF: 0.0976 AC: 1617 AN: 16564

East Asian (EAS) AF: 0.220 AC: 7222 AN: 32884

South Asian (SAS) AF: 0.218 AC: 12439 AN: 57020

European-Finnish (FIN) AF: 0.304 AC: 10350 AN: 34100

Middle Eastern (MID) AF: 0.0814 AC: 212 AN: 2604

European-Non Finnish (NFE) AF: 0.162 AC: 79609 AN: 492652

Other (OTH) AF: 0.170 AC: 5952 AN: 35032

GnomAD4 genome AF: 0.169 AC: 25767 AN: 152226 Hom.: 2493 Cov.: 33 AF XY: 0.178 AC XY: 13227 AN XY: 74420

African (AFR) AF: 0.113 AC: 4692 AN: 41546

American (AMR) AF: 0.207 AC: 3166 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1091 AN: 5170

South Asian (SAS) AF: 0.216 AC: 1040 AN: 4822

European-Finnish (FIN) AF: 0.321 AC: 3404 AN: 10596

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11479 AN: 68004

Other (OTH) AF: 0.158 AC: 334 AN: 2116

Alfa AF: 0.161 Hom.: 4184

Bravo AF: 0.157

Asia WGS AF: 0.275 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.59
PhyloP100		0.16
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: rs7219550; hg19: chr17-7401671;