5-90501935-G-A

Variant names:

• chr5-90501935-G-A
• rs200186119
• NM_006467.3:c.385G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_006467.3(POLR3G):​c.385G>A​(p.Ala129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: POLR3G NM_006467.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.43

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 5-90501935-G-A is Benign according to our data. Variant chr5-90501935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2409061.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3G	NM_006467.3	c.385G>A	p.Ala129Thr	missense_variant	Exon 6 of 8	ENST00000651687.1	NP_006458.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3G	ENST00000651687.1	c.385G>A	p.Ala129Thr	missense_variant	Exon 6 of 8		NM_006467.3	ENSP00000498469.1
POLR3G	ENST00000504930.5	c.385G>A	p.Ala129Thr	missense_variant	Exon 6 of 8	2		ENSP00000421637.1
POLR3G	ENST00000503373.5	c.385G>A	p.Ala129Thr	missense_variant	Exon 6 of 8	4		ENSP00000422892.1
POLR3G	ENST00000399107.6	n.414G>A		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000382058.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 248640 AF XY: 0.0000370

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461172 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 726906

African (AFR) AF: 0.000598 AC: 20 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111588

Other (OTH) AF: 0.0000994 AC: 6 AN: 60348

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74376

African (AFR) AF: 0.000554 AC: 23 AN: 41490

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.000535 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 06, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.060
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.51
DANN	Benign	0.37
DEOGEN2	Benign	0.0029	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.53	T;T;.
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.78	.;N;N
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.73	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.14	.;B;B
Vest4		0.053
MVP		0.12
MPC		0.074
ClinPred		0.014	T
GERP RS		-3.8
Varity_R		0.022
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -29

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

Publications

LitVar

Other links and lift over

dbSNP: rs200186119; hg19: chr5-89797752; COSMIC: COSV67626382; COSMIC: COSV67626382;