chr1-145977093-G-C

Variant names:

• chr1-145977093-G-C
• rs782502275
• NM_032305.3:c.266G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032305.3(POLR3GL):​c.266G>C​(p.Arg89Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R89H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLR3GL NM_032305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.08
• Publications: 0 publications found

Genes affected

POLR3GL (HGNC:28466): (RNA polymerase III subunit GL) Predicted to enable chromatin binding activity. Involved in transcription by RNA polymerase III. Located in nucleus. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000280778 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3GL	NM_032305.3	c.266G>C	p.Arg89Pro	missense_variant	Exon 4 of 8	ENST00000369314.2	NP_115681.1
POLR3GL	NM_001330685.2	c.257-390G>C		intron_variant	Intron 3 of 6		NP_001317614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3GL	ENST00000369314.2	c.266G>C	p.Arg89Pro	missense_variant	Exon 4 of 8	1	NM_032305.3	ENSP00000358320.1
ENSG00000280778	ENST00000625258.1	c.-20G>C		5_prime_UTR_variant	Exon 2 of 4	5		ENSP00000487094.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727164

⚠️ 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: 33472

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Pathogenic	0.90	D
PhyloP100		8.1
PROVEAN	Pathogenic	-5.8	D
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.95
gMVP		0.92

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: rs782502275; hg19: chr1-145457994;