chr6-110967547-C-G

Variant names:

• chr6-110967547-C-G
• rs1239917299
• NM_138408.4:c.399C>G

Variant summary

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

The NM_138408.4(GTF3C6):​c.399C>G​(p.Phe133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,536 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GTF3C6 NM_138408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.977
• Publications: 0 publications found

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]

ENSG00000298854 (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=0.16875064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C6	NM_138408.4	MANE Select	c.399C>G	p.Phe133Leu	missense	Exon 6 of 6	NP_612417.1	Q969F1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C6	ENST00000329970.8	TSL:1 MANE Select	c.399C>G	p.Phe133Leu	missense	Exon 6 of 6	ENSP00000357863.4	Q969F1
	GTF3C6	ENST00000935770.1		c.537C>G	p.Phe179Leu	missense	Exon 7 of 7	ENSP00000605829.1
	GTF3C6	ENST00000935771.1		c.456C>G	p.Phe152Leu	missense	Exon 6 of 6	ENSP00000605830.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461366 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111796

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.98
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.028	D
Sift4G	Benign	0.11	T
Polyphen		0.17	B
Vest4		0.46
MutPred		0.42		Gain of sheet (P = 0.0827)
MVP		0.095
MPC		0.47
ClinPred		0.89	D
GERP RS		2.5
Varity_R		0.10
gMVP		0.21
Mutation Taster		=81/19	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: rs1239917299; hg19: chr6-111288750;