1-145826496-A-T

Variant names:

• chr1-145826496-A-T
• rs1553725761
• NM_006468.8:c.190A>T

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.190A>T​(p.Ser64Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S64T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR3C NM_006468.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.333
• 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=0.22428805).

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.190A>T	p.Ser64Cys	missense	Exon 3 of 15	NP_006459.3
	POLR3C	NM_001303456.1		c.229A>T	p.Ser77Cys	missense	Exon 3 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.190A>T	p.Ser64Cys	missense	Exon 3 of 15	ENSP00000334564.3	Q9BUI4
	POLR3C	ENST00000369294.5	TSL:1	c.190A>T	p.Ser64Cys	missense	Exon 3 of 12	ENSP00000358300.1	E9PHH9
	POLR3C	ENST00000698751.1		c.190A>T	p.Ser64Cys	missense	Exon 3 of 15	ENSP00000513913.1	Q9BUI4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247062 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461282 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726928

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_noAF	Benign	-0.80
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.22	T
PhyloP100		0.33
PROVEAN	Uncertain	-2.6	D
Sift	Benign	0.052	T
Sift4G	Benign	0.064	T
Vest4		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.79

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: rs1553725761; hg19: chr1-145608617;