rs782747011

Variant names:

• chr1-145977137-A-C
• rs782747011
• NM_032305.3:c.310A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-145977137-A-C
• chr1-145977137-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032305.3(POLR3GL):​c.310A>C​(p.Ile104Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000892 in 1,613,652 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. I104V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000094 (2 hom.)
• Consequence: POLR3GL NM_032305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08990461).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3GL	NM_032305.3	c.310A>C	p.Ile104Leu	missense_variant	Exon 4 of 8	ENST00000369314.2	NP_115681.1
POLR3GL	NM_001330685.2	c.257-346A>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.310A>C	p.Ile104Leu	missense_variant	Exon 4 of 8	1	NM_032305.3	ENSP00000358320.1
ENSG00000280778	ENST00000625258.1	c.25A>C	p.Ile9Leu	missense_variant	Exon 2 of 4	5		ENSP00000487094.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251492 AF XY: 0.000228

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000944 AC: 138 AN: 1461582 Hom.: 2 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 727116

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: 39696

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111730

Other (OTH) AF: 0.0000497 AC: 3 AN: 60386

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310A>C (p.I104L) alteration is located in exon 4 (coding exon 3) of the POLR3GL gene. This alteration results from a A to C substitution at nucleotide position 310, causing the isoleucine (I) at amino acid position 104 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.032	.;T
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.090	T;T
PhyloP100		4.5
PROVEAN	Benign	-0.45	.;N
Sift	Benign	1.0	.;T
Sift4G	Benign	0.37	T;T
Vest4		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs782747011; hg19: chr1-145457950;