Genetic Variant GTF3C6:p.Arg52Thr (chr6-110960430-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138408.4(GTF3C6):c.155G>C(p.Arg52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GTF3C6
NM_138408.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

GTF3C6 (HGNC:20872): (general transcription factor IIIC subunit 6) RNA polymerases are unable to initiate RNA synthesis in the absence of additional proteins called general transcription factors (GTFs). GTFs assemble in a complex on the DNA promoter and recruit the RNA polymerase. GTF3C family proteins (e.g., GTF3C1, MIM 603246) are essential for RNA polymerase III to make a number of small nuclear and cytoplasmic RNAs, including 5S RNA (MIM 180420), tRNA, and adenovirus-associated (VA) RNA of both cellular and viral origin.[supplied by OMIM, Mar 2008]

GTF3C6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4189468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF3C6	NM_138408.4 link	c.155G>C	p.Arg52Thr	missense_variant	Exon 3 of 6	ENST00000329970.8	NP_612417.1	Q969F1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF3C6	ENST00000329970.8 link	c.155G>C	p.Arg52Thr	missense_variant	Exon 3 of 6	1	NM_138408.4	ENSP00000357863.4		Q969F1
GTF3C6	ENST00000480191.1 link	n.213G>C		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155G>C (p.R52T) alteration is located in exon 3 (coding exon 3) of the GTF3C6 gene. This alteration results from a G to C substitution at nucleotide position 155, causing the arginine (R) at amino acid position 52 to be replaced by a threonine (T). 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

Uncertain

0.38

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.092

Eigen

Benign

0.098

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0049

MetaRNN

Benign

0.42

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.25

Sift

Uncertain

0.013

Sift4G

Uncertain

0.014

Polyphen

0.84

Vest4

0.51

MutPred

0.49

Gain of sheet (P = 0.0827);

MVP

0.33

MPC

0.79

ClinPred

0.96

GERP RS

4.0

Varity_R

0.25

gMVP

0.48

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over