2-196771932-C-T

Variant names:

• chr2-196771932-C-T
• NM_012086.5:c.2076G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012086.5(GTF3C3):​c.2076G>A​(p.Met692Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF3C3 NM_012086.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF3C3	NM_012086.5	c.2076G>A	p.Met692Ile	missense_variant	Exon 15 of 18	ENST00000263956.8	NP_036218.1
GTF3C3	XM_005246965.5	c.900G>A	p.Met300Ile	missense_variant	Exon 8 of 11		XP_005247022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF3C3	ENST00000263956.8	c.2076G>A	p.Met692Ile	missense_variant	Exon 15 of 18	1	NM_012086.5	ENSP00000263956.3
GTF3C3	ENST00000651042.1	n.*408G>A		non_coding_transcript_exon_variant	Exon 16 of 19			ENSP00000499170.1
GTF3C3	ENST00000651042.1	n.*408G>A		3_prime_UTR_variant	Exon 16 of 19			ENSP00000499170.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456728 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2076G>A (p.M692I) alteration is located in exon 15 (coding exon 15) of the GTF3C3 gene. This alteration results from a G to A substitution at nucleotide position 2076, causing the methionine (M) at amino acid position 692 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.094
Sift	Benign	0.33	T
Sift4G	Uncertain	0.015	D
Polyphen		0.50	P
Vest4		0.56
MutPred		0.49		Loss of catalytic residue at M692 (P = 0.004);
MVP		0.61
MPC		0.43
ClinPred		0.59	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-197636656;