2-196773130-C-T

Variant summary

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

The NM_012086.5(GTF3C3):​c.1855G>A​(p.Val619Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,605,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GTF3C3
NM_012086.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GTF3C3NM_012086.5 linkc.1855G>A p.Val619Ile missense_variant Exon 14 of 18 ENST00000263956.8 NP_036218.1 Q9Y5Q9-1
GTF3C3XM_005246965.5 linkc.679G>A p.Val227Ile missense_variant Exon 7 of 11 XP_005247022.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GTF3C3ENST00000263956.8 linkc.1855G>A p.Val619Ile missense_variant Exon 14 of 18 1 NM_012086.5 ENSP00000263956.3 Q9Y5Q9-1
GTF3C3ENST00000416690.5 linkc.202G>A p.Val68Ile missense_variant Exon 4 of 4 3 ENSP00000391724.1 H7BZV8
GTF3C3ENST00000651042.1 linkn.*187G>A non_coding_transcript_exon_variant Exon 15 of 19 ENSP00000499170.1 A0A494C1S7
GTF3C3ENST00000651042.1 linkn.*187G>A 3_prime_UTR_variant Exon 15 of 19 ENSP00000499170.1 A0A494C1S7

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000813
AC:
2
AN:
245992
Hom.:
0
AF XY:
0.0000151
AC XY:
2
AN XY:
132816
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000892
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.00000550
AC:
8
AN:
1453478
Hom.:
0
Cov.:
28
AF XY:
0.00000691
AC XY:
5
AN XY:
723164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000691
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000506
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000982

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1855G>A (p.V619I) alteration is located in exon 14 (coding exon 14) of the GTF3C3 gene. This alteration results from a G to A substitution at nucleotide position 1855, causing the valine (V) at amino acid position 619 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
Benign
0.11
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T
Eigen
Benign
0.088
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.15
N
REVEL
Benign
0.13
Sift
Benign
0.39
T
Sift4G
Benign
0.51
T
Polyphen
0.70
P
Vest4
0.70
MutPred
0.42
Loss of ubiquitination at K622 (P = 0.1306);
MVP
0.45
MPC
0.47
ClinPred
0.32
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.090
gMVP
0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1054636315; hg19: chr2-197637854; COSMIC: COSV55835213; COSMIC: COSV55835213; API