5-90501917-C-T

Position:

• chr5-90501917-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006467.3(POLR3G):​c.367C>T​(p.Pro123Ser) 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 1,461,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR3G NM_006467.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

Genes affected

POLR3G (HGNC:30075): (RNA polymerase III subunit G) Enables chromatin binding activity. Involved in positive regulation of innate immune response; positive regulation of interferon-beta production; and transcription by RNA polymerase III. Acts upstream of or within cell population proliferation. Located in cytosol and nuclear body. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018274754).
• BP6: Variant 5-90501917-C-T is Benign according to our data. Variant chr5-90501917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2474328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3G	NM_006467.3	c.367C>T	p.Pro123Ser	missense_variant	6/8	ENST00000651687.1	NP_006458.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3G	ENST00000651687.1	c.367C>T	p.Pro123Ser	missense_variant	6/8		NM_006467.3	ENSP00000498469.1
POLR3G	ENST00000504930.5	c.367C>T	p.Pro123Ser	missense_variant	6/8	2		ENSP00000421637.1
POLR3G	ENST00000503373.5	c.367C>T	p.Pro123Ser	missense_variant	6/8	4		ENSP00000422892.1
POLR3G	ENST00000399107.6	n.396C>T		non_coding_transcript_exon_variant	6/8	2		ENSP00000382058.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461060 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.1
DANN	Benign	0.40
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.51	T;T;.
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	.;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0060	.;B;B
Vest4		0.083
MutPred		0.21		Gain of phosphorylation at P123 (P = 0.0073);Gain of phosphorylation at P123 (P = 0.0073);Gain of phosphorylation at P123 (P = 0.0073);
MVP		0.14
MPC		0.076
ClinPred		0.025	T
GERP RS		1.6
Varity_R		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-89797734;