2-196766579-G-A

Variant names:

• chr2-196766579-G-A
• rs144612738
• NM_012086.5:c.2524C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012086.5(GTF3C3):​c.2524C>T​(p.Pro842Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P842A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF3C3 NM_012086.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4019022).

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.2524C>T	p.Pro842Ser	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.2524C>T	p.Pro842Ser	missense	Exon 17 of 18	ENSP00000263956.3	Q9Y5Q9-1
	GTF3C3	ENST00000929329.1		c.2551C>T	p.Pro851Ser	missense	Exon 17 of 18	ENSP00000599388.1
	GTF3C3	ENST00000929328.1		c.2548C>T	p.Pro850Ser	missense	Exon 18 of 19	ENSP00000599387.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250062 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458028 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725382

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000225 AC: 1 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109718

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Polyphen		0.51	P
Vest4		0.42
MutPred		0.55		Loss of catalytic residue at P841 (P = 0.0212)
MVP		0.61
MPC		0.45
ClinPred		0.67	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.38
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144612738; hg19: chr2-197631303;