rs1554837782

Variant names:

• chr10-77984299-C-T
• rs1554837782
• NM_007055.4:c.3243-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_007055.4(POLR3A):​c.3243-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,449,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: POLR3A NM_007055.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.42
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• odontoleukodystrophy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Wiedemann-Rautenstrauch syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor-ataxia-central hypomyelination syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022525761 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -27, new splice context is: agcctcctcccttgtgctAGtgc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-77984299-C-T is Pathogenic according to our data. Variant chr10-77984299-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 436361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.3243-1G>A		splice_acceptor_variant, intron_variant	Intron 24 of 30	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.3243-1G>A		splice_acceptor_variant, intron_variant	Intron 24 of 30	1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1449602 Hom.: 0 Cov.: 28 AF XY: 0.0000125 AC XY: 9 AN XY: 722068

African (AFR) AF: 0.00 AC: 0 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1101138

Other (OTH) AF: 0.0000167 AC: 1 AN: 59946

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Pathogenic:1

Jul 26, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leukodystrophy Pathogenic:1

Apr 30, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.3243-1G>A variant in POLR3A has not been previously reported in the literature in individuals with with POLR3A-related disorders, but has been identified in 0.002% (18/1169154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1554837782). 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 (VCV000436361.6) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago). This variant is located in the 5' splice region. This variant is located in the 5' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 17 bases from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. 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: PVS1, PM2_supporting (Richards 2015).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.4
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: -18
DS_AL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1554837782; hg19: chr10-79744057;