rs890755853

Positions:

• chr10-78021855-C-A

Variant summary

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

The NM_007055.4(POLR3A):​c.1048+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: POLR3A NM_007055.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.724

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]

POLR3A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78021855-C-A is Pathogenic according to our data. Variant chr10-78021855-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78021855-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.1048+5G>T		splice_region_variant, intron_variant		ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.1048+5G>T		splice_region_variant, intron_variant		1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251282 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461148 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 726902

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000487 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2024	The c.1048+5G>T variant in POLR3A has been reported in 3 individuals with POLR3A-related disorders (PMID: 28459997, 30323018, 31940116, 33972714) and has been identified in 0.0009% (1/113660) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs890755853). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 549560) and has been interpreted as likely pathogenic or pathogenic by Tartaglia Lab, Genetics and Rare Diseases Research Division (Bambino Gesu' Children's Hospital) and OMIM. Of the 3 affected individuals, 2 were compound heterozygotes that carried reported pathogenic variants in trans, which increases the likelihood that the c.1048+5G>T variant is pathogenic (VariationID: 445922, 449556; PMID: 28459997, 30323018, 31940116, 33972714). In vitro functional studies provide some evidence that the c.1048+5G>T variant may impact protein function (PMID: 28459997, 30323018). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PS3_moderate, PM3_strong, PM2_supporting, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 01, 2022	This sequence change in POLR3A is an intronic variant located in intron 7. This variant is present in a single individual in gnomAD v2.1 (1/113,660 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected in at least two individuals with spastic ataxia and one individual with Wiedemann-rautenstrauch syndrome. All individuals were compound heterozygous for the variant and a pathogenic variant and two of those were confirmed in trans by parental/family testing (PMID: 28459997, 30323018, 33972714). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the donor splice site of intron 7 of POLR3A. This prediction is confirmed by RT-PCR. The assay demonstrated that the variant impacts splicing by inclusion of all 177 bp of intron 7 (PMID: 28459997, 30323018, 33972714). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM3_Strong, PM2_Supporting, PP3. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

Neonatal pseudo-hydrocephalic progeroid syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	Apr 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.84
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.040		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: rs890755853; hg19: chr10-79781613;