rs267608677

Positions:

• chr10-78009519-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_007055.4(POLR3A):​c.1909+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLR3A NM_007055.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -0.106

Genes affected

POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78009519-C-T is Pathogenic according to our data. Variant chr10-78009519-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78009519-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.1909+18G>A		intron_variant		ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.1909+18G>A		intron_variant		1	NM_007055.4	ENSP00000361446	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152218 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 09, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 09, 2020	This intronic variant (c.1909+18G>A) has not been observed in population databases (gnomAD), but several cases have been reported in the literature (PMID 21855841, PMID 27612211, PMID 30323018, PMID 12605447). Functional studies have not been published, although RNA analysis indicated altered splicing and retention of intronic nucletotides, leading to a shift in reading frame. In our laboratory, it was found homozygous in two affected siblings and heterozygous in each of their parents (with consanguinity reported). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 21855841). ClinVar contains an entry for this variant (Variation ID: 31144). This variant is also known as c.2003+18G>A and c.1911+18C>T. This variant has been observed in individual(s) with leukodystrophy with oligodontia and/or Wiedemann–Rautenstrauch syndrome (PMID: 21855841, 27612211). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. -

Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608677; hg19: chr10-79769277;