17-7495924-CCTTT-C

Variant names:

• chr17-7495924-CCTTT-C
• rs3216887
• NM_000937.5:c.94-8_94-5delCTTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000937.5(POLR2A):​c.94-8_94-5delCTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 1,613,604 control chromosomes in the GnomAD database, including 1,788 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (410 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1378 hom.)
• Consequence: POLR2A NM_000937.5 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.417
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Broad Center for Mendelian Genomics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 17-7495924-CCTTT-C is Benign according to our data. Variant chr17-7495924-CCTTT-C is described in ClinVar as Benign. ClinVar VariationId is 3056317.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000937.5. 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
	POLR2A	NM_000937.5	MANE Select	c.94-8_94-5delCTTT		splice_region intron	N/A	NP_000928.1	A0AAG2TJB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2A	ENST00000674977.2		c.94-16_94-13delCTTT		intron	N/A	ENSP00000502190.2	A0A6Q8PGB0
	POLR2A	ENST00000572844.1	TSL:1	n.239-16_239-13delCTTT		intron	N/A
	POLR2A	ENST00000617998.6	TSL:1	n.493-16_493-13delCTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8988 AN: 152102 Hom.: 396 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0361 AC: 9082 AN: 251270 AF XY: 0.0341

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0567

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0378 AC: 55244 AN: 1461384 Hom.: 1378 AF XY: 0.0366 AC XY: 26633 AN XY: 727030

African (AFR) AF: 0.134 AC: 4497 AN: 33446

American (AMR) AF: 0.0206 AC: 920 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 1216 AN: 26122

East Asian (EAS) AF: 0.0713 AC: 2829 AN: 39696

South Asian (SAS) AF: 0.0132 AC: 1137 AN: 86252

European-Finnish (FIN) AF: 0.0259 AC: 1386 AN: 53416

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5768

European-Non Finnish (NFE) AF: 0.0364 AC: 40428 AN: 1111596

Other (OTH) AF: 0.0447 AC: 2696 AN: 60370

GnomAD4 genome AF: 0.0593 AC: 9028 AN: 152220 Hom.: 410 Cov.: 31 AF XY: 0.0574 AC XY: 4270 AN XY: 74424

African (AFR) AF: 0.125 AC: 5202 AN: 41510

American (AMR) AF: 0.0314 AC: 480 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3470

East Asian (EAS) AF: 0.0582 AC: 301 AN: 5176

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4812

European-Finnish (FIN) AF: 0.0286 AC: 304 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2416 AN: 68020

Other (OTH) AF: 0.0455 AC: 96 AN: 2110

Alfa AF: 0.0470 Hom.: 46

Bravo AF: 0.0628

Asia WGS AF: 0.0450 AC: 155 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	POLR2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs3216887; hg19: chr17-7399243;