2-196766579-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012086.5(GTF3C3):​c.2524C>G​(p.Pro842Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,610,272 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: GTF3C3 NM_012086.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008250058).
• BP6: Variant 2-196766579-G-C is Benign according to our data. Variant chr2-196766579-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3037273.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

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>G	p.Pro842Ala	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>G	p.Pro842Ala	missense	Exon 17 of 18	ENSP00000263956.3	Q9Y5Q9-1
	GTF3C3	ENST00000929329.1		c.2551C>G	p.Pro851Ala	missense	Exon 17 of 18	ENSP00000599388.1
	GTF3C3	ENST00000929328.1		c.2548C>G	p.Pro850Ala	missense	Exon 18 of 19	ENSP00000599387.1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00184 AC: 460 AN: 250062 AF XY: 0.00188

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00341 AC: 4976 AN: 1457978 Hom.: 12 Cov.: 29 AF XY: 0.00333 AC XY: 2413 AN XY: 725366

African (AFR) AF: 0.000509 AC: 17 AN: 33376

American (AMR) AF: 0.000428 AC: 19 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: 0.000630 AC: 54 AN: 85732

European-Finnish (FIN) AF: 0.000657 AC: 35 AN: 53270

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

European-Non Finnish (NFE) AF: 0.00425 AC: 4719 AN: 1109668

Other (OTH) AF: 0.00219 AC: 132 AN: 60140

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00180 AC XY: 134 AN XY: 74482

African (AFR) AF: 0.000626 AC: 26 AN: 41556

American (AMR) AF: 0.000654 AC: 10 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00362 AC: 246 AN: 68028

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00193

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GTF3C3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.054
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.094
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.13	B
Vest4		0.27
MVP		0.60
MPC		0.37
ClinPred		0.045	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.26
Mutation Taster		=88/12	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: rs144612738; hg19: chr2-197631303; COSMIC: COSV105060670; COSMIC: COSV105060670;