rs191875469

Variant names:

• chr10-78009515-C-T
• rs191875469
• NM_007055.4:c.1909+22G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3 PP5_Very_Strong BP4 BS2_Supporting

The NM_007055.4(POLR3A):​c.1909+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001134970: Functional studies suggest this variant generates a "leaky" cryptic donor site that results in the inclusion of part of intron 14 (Minnerop et al., 2017)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (10 hom.)
• Consequence: POLR3A NM_007055.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 U:2 O:2
• Conservation: PhyloP100: -0.768
• Publications: 33 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: Orphanet, Illumina
• POLR3A-related disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Wiedemann-Rautenstrauch syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, 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 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001134970: Functional studies suggest this variant generates a "leaky" cryptic donor site that results in the inclusion of part of intron 14 (Minnerop et al., 2017); SCV001583974: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28459997, 30323018).; SCV002557627: "Functional analysis of patient leucocyte-derived cDNA, has demonstrated that this variant results in the leaky inclusion of 19 nucleotides in intron 14. This results in a shift in the reading frame, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (PMID: 28459997)."; SCV004232684: "In vitro functional studies provide some evidence that the c.1909+22G>A variant may impact protein function." PMID:28459997; SCV005199891: The variant adds 19 bases of intron 14 to the transcript and creates an alternate splice site, resulting in premature truncation. The change has been reported in the literature, and published studies indicate a decrease in POLR3A protein (PMID 28459997, PMID 30323018, PMID 21855841).; SCV001423749: Evaluation of PCR products from affected individuals and healthy controls indicated that the variant affects splicing of exon 14, although this effect may be incomplete. In addition, inhibition of nonsense medicated mRNA decay in fibroblasts from affected individuals suggested the aberrantly spliced transcript due to the c.1909+22G>A variant is subject to nonsense mediated decay. In addition, gene and protein expression were reduced in the presence of the variant compared to controls (Minnerop et al. 2017).; SCV002754528: Functional studies demonstrate that this variant disrupts mRNA splicing leading to premature termination and nonsense-mediated mRNA decay (PMID: 28459997, 30323018) (PVS1).; SCV004116147: Additional studies indicate that the c.1909+22G>A variant, which is postulated to be a hypomorphic variant, generates a novel cryptic splice donor site, leading to a frameshift and premature protein termination; the resulting transcript is subject to nonsense-mediated mRNA decay (Minnerop et al. 2017. PubMed ID: 28459997).; SCV003718066: Functional RNA studies of c.1909+22G>A demonstrated a mild effect on splicing due to activation of an out of frame cryptic splice site which resulted in partial intron 14 retention and a transcript that was partially degraded by nonsense mediated decay (Minnerop, 2017; Rydning, 2019; Morales-Rosado, 2020). RNA studies in two patients who harbored the complex allele [c.1909+22G>A; c.3337-11T>C] demonstrated that both variants resulted in aberrant splicing and thus the additive effect on splicing was proposed to be a greater loss of function allele associated with a more severe phenotype (Paolacci, 2018).; SCV004122078: At least one publication reports experimental evidence that this variant affects mRNA splicing and suggests this variant activates a "leaky" cryptic donor site that results in the inclusion of part of intron 14, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (Minnerop_2017, Paolacci_ 2018).; SCV004812517: The assay demonstrated that the variant impacts splicing by activation of a leaky cryptic donor site leading to 19 bp intron 14 inclusion (p.Tyr637Cysfs*14). PMID: 28459997
• PP5: Variant 10-78009515-C-T is Pathogenic according to our data. Variant chr10-78009515-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 445922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007055.4. 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
	POLR3A	NM_007055.4	MANE Select	c.1909+22G>A		intron	N/A	NP_008986.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3A	ENST00000372371.8	TSL:1 MANE Select	c.1909+22G>A		intron	N/A	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.1909+22G>A		intron	N/A	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.1768+22G>A		intron	N/A	ENSP00000513898.1	A0A8V8TNX3

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00137 AC: 345 AN: 251418 AF XY: 0.00140

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00250 AC: 3653 AN: 1461850 Hom.: 10 Cov.: 32 AF XY: 0.00243 AC XY: 1764 AN XY: 727226

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86252

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.00302 AC: 3360 AN: 1111984

Other (OTH) AF: 0.00177 AC: 107 AN: 60394

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74498

African (AFR) AF: 0.000577 AC: 24 AN: 41584

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.00150

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	1	-	Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (12)
9	-	-	not provided (9)
4	-	-	Neonatal pseudo-hydrocephalic progeroid syndrome (4)
4	-	-	POLR3A-related disorder (4)
1	-	-	Hereditary ataxia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Movement disorder (1)
-	1	-	not specified (1)
1	-	-	POLR-related leukodystrophy (1)
1	-	-	POLR3A-related neurological disorders (1)
1	-	-	Spastic ataxia (1)
-	-	-	Neonatal pseudo-hydrocephalic progeroid syndrome;C3280644:Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;CN034185:Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.63
PhyloP100		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs191875469;

hg19: chr10-79769273;