10-77985959-GC-CA

Variant names:

• chr10-77985959-GC-CA
• NM_007055.4:c.3014_3015delGCinsTG
• POLR3A p.Arg1005Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1_Moderate PM5

The NM_007055.4(POLR3A):​c.3014_3015delGCinsTG​(p.Arg1005Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. 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: Not reported in ClinVar
• 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: Orphanet, Illumina
• POLR3A-related disorder

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_007055.4 (POLR3A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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.

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.3014_3015delGCinsTG	p.Arg1005Leu	missense	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.3014_3015delGCinsTG	p.Arg1005Leu	missense	N/A	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.3014_3015delGCinsTG	p.Arg1005Leu	missense	N/A	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.2873_2874delGCinsTG	p.Arg958Leu	missense	N/A	ENSP00000513898.1	A0A8V8TNX3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

hg19: chr10-79745717;