2-196766683-C-G

Variant names:

• chr2-196766683-C-G
• rs1212578042
• NM_012086.5:c.2420G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_012086.5(GTF3C3):​c.2420G>C​(p.Arg807Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R807H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GTF3C3 NM_012086.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

Genes affected

GTF3C3 (HGNC:4666): (general transcription factor IIIC subunit 3) The protein encoded by this gene is part of the TFIIIC2 complex, which binds to the promoters of small nuclear and cytoplasmic RNA genes in order to recruit RNA polymerase III. The TFIIIC2 complex is composed of six subunits. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GTF3C3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-196766683-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3899894.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012086.5. 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
	GTF3C3	NM_012086.5	MANE Select	c.2420G>C	p.Arg807Pro	missense	Exon 17 of 18	NP_036218.1	Q9Y5Q9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C3	ENST00000263956.8	TSL:1 MANE Select	c.2420G>C	p.Arg807Pro	missense	Exon 17 of 18	ENSP00000263956.3	Q9Y5Q9-1
	GTF3C3	ENST00000929329.1		c.2447G>C	p.Arg816Pro	missense	Exon 17 of 18	ENSP00000599388.1
	GTF3C3	ENST00000929328.1		c.2444G>C	p.Arg815Pro	missense	Exon 18 of 19	ENSP00000599387.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151882 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460582 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726610

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111158

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74176

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.84		Gain of glycosylation at R807 (P = 0.1366)
MVP		0.65
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.90
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs1212578042; hg19: chr2-197631407;