1-145978030-G-C

Variant names:

• chr1-145978030-G-C
• rs374164450
• NM_032305.3:c.504G>C

Variant summary

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

The NM_032305.3(POLR3GL):​c.504G>C​(p.Glu168Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLR3GL NM_032305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10730761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3GL	NM_032305.3	c.504G>C	p.Glu168Asp	missense_variant	Exon 7 of 8	ENST00000369314.2	NP_115681.1
POLR3GL	NM_001330685.2	c.435G>C	p.Glu145Asp	missense_variant	Exon 6 of 7		NP_001317614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3GL	ENST00000369314.2	c.504G>C	p.Glu168Asp	missense_variant	Exon 7 of 8	1	NM_032305.3	ENSP00000358320.1
ENSG00000280778	ENST00000625258.1	c.*219G>C		downstream_gene_variant		5		ENSP00000487094.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.504G>C (p.E168D) alteration is located in exon 7 (coding exon 6) of the POLR3GL gene. This alteration results from a G to C substitution at nucleotide position 504, causing the glutamic acid (E) at amino acid position 168 to be replaced by an aspartic acid (D). 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	0.095
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;T
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.11	T;T
PhyloP100		2.1
PROVEAN	Benign	-0.76	N;N
Sift	Benign	0.13	T;T
Sift4G	Benign	0.19	T;T
Vest4		0.15
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
gMVP		0.034
Mutation Taster		=96/4	polymorphism

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: rs374164450; hg19: chr1-145457057;