6-110962445-A-C

Variant names:

• chr6-110962445-A-C
• rs1771172681
• NM_138408.4:c.301A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138408.4(GTF3C6):​c.301A>C​(p.Lys101Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GTF3C6 NM_138408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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.301A>C	p.Lys101Gln	missense	Exon 5 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.301A>C	p.Lys101Gln	missense	Exon 5 of 6	ENSP00000357863.4	Q969F1
	GTF3C6	ENST00000935770.1		c.439A>C	p.Lys147Gln	missense	Exon 6 of 7	ENSP00000605829.1
	GTF3C6	ENST00000935771.1		c.358A>C	p.Lys120Gln	missense	Exon 5 of 6	ENSP00000605830.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460312 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726578

African (AFR) AF: 0.00 AC: 0 AN: 33446

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

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

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110624

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

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

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

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	0.82
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.22
MPC		0.86
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.72
Mutation Taster		=45/55	disease causing

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: rs1771172681; hg19: chr6-111283648;