1-145826993-C-G

Variant names:

• chr1-145826993-C-G
• rs368282627
• NM_006468.8:c.577C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006468.8(POLR3C):​c.577C>G​(p.Leu193Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L193F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLR3C NM_006468.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

Genes affected

POLR3C (HGNC:30076): (RNA polymerase III subunit C) Enables single-stranded DNA binding activity. Involved in positive regulation of innate immune response and positive regulation of interferon-beta production. Located in nucleoplasm. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101518005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006468.8. 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
	POLR3C	NM_006468.8	MANE Select	c.577C>G	p.Leu193Val	missense	Exon 4 of 15	NP_006459.3
	POLR3C	NM_001303456.1		c.616C>G	p.Leu206Val	missense	Exon 4 of 15	NP_001290385.1	Q9BUI4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3C	ENST00000334163.4	TSL:1 MANE Select	c.577C>G	p.Leu193Val	missense	Exon 4 of 15	ENSP00000334564.3	Q9BUI4
	POLR3C	ENST00000369294.5	TSL:1	c.577C>G	p.Leu193Val	missense	Exon 4 of 12	ENSP00000358300.1	E9PHH9
	POLR3C	ENST00000698751.1		c.577C>G	p.Leu193Val	missense	Exon 4 of 15	ENSP00000513913.1	Q9BUI4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724770

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 42896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110556

Other (OTH) AF: 0.00 AC: 0 AN: 60230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.010	T
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.10	T
PhyloP100		1.5
PROVEAN	Benign	-0.36	N
Sift	Benign	0.34	T
Sift4G	Benign	0.48	T
Vest4		0.22
gMVP		0.65

Splicing

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

Other links and lift over

dbSNP: rs368282627; hg19: chr1-145608120; COSMIC: COSV61937400; COSMIC: COSV61937400;