10-77985960-C-A

Variant names:

• chr10-77985960-C-A
• rs200118797
• NM_007055.4:c.3014G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_007055.4(POLR3A):​c.3014G>T​(p.Arg1005Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1005H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLR3A NM_007055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.49
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-77985960-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41246.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 10-77985960-C-A is Pathogenic according to our data. Variant chr10-77985960-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1328129.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.3014G>T	p.Arg1005Leu	missense_variant	Exon 23 of 31	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.3014G>T	p.Arg1005Leu	missense_variant	Exon 23 of 31	1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

POLR3A-related neurological disorders Pathogenic:1

Oct 13, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLR3A c.3014G>T (p.Arg1005Leu) variant is a missense variant. While this variant has not been reported in the literature, other variants at the Arg1005 residue have been described in individuals with POLR3A-related neurological disorders. This includes at least four individuals with the p.Arg1005Cys variant and three individuals with the p.Arg1005His variant, all present in a compound heterozygous state (Bernard et al. 2011; Saitsu et al. 2011; Potic et al. 2012; Daoud et al. 2013; Wolf et al. 2014). The p.Arg1005Leu variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. While no functional studies have been performed for the p.Arg1005Leu variant, in silico tools predict a deleterious effect of the variant. Based on the available evidence, the p.Arg1005Leu variant is classified as likely pathogenic for POLR3A-related neurological disorders. -

not provided Uncertain:1

Apr 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.78
Sift	Benign	0.038	D
Sift4G	Benign	0.067	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.65		Loss of helix (P = 0.0558);
MVP		0.89
MPC		0.58
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.86
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200118797; hg19: chr10-79745718;