17-7496056-G-A

Position:

• chr17-7496056-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PP2 PP3_Moderate BS2

The NM_000937.5(POLR2A):​c.209G>A​(p.Arg70His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: POLR2A NM_000937.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR2A. . Trascript score misZ 9.1922 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, autism, susceptibility to, 15.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.209G>A	p.Arg70His	missense_variant	2/30	ENST00000643490.2	NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000674977.2	c.209G>A	p.Arg70His	missense_variant	2/30			ENSP00000502190	P1
POLR2A	ENST00000572844.1	n.354G>A		non_coding_transcript_exon_variant	2/10	1
POLR2A	ENST00000617998.6	n.608G>A		non_coding_transcript_exon_variant	2/29	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 244062 Hom.: 0 AF XY: 0.0000302 AC XY: 4 AN XY: 132442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000594

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456644 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 4 AN XY: 724566

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jul 22, 2023

The observed missense c.209G>Ap.Arg70His variant in POLR2A gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Arg70His variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on POLR2A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 70 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.046	D
Vest4		0.80
MutPred		0.49		Loss of phosphorylation at T73 (P = 0.0782);
MVP		0.85
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs1234085512; hg19: chr17-7399375; COSMIC: COSV104400891; COSMIC: COSV104400891;