19-6380574-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002096.3(GTF2F1):​c.1348G>A​(p.Gly450Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GTF2F1
NM_002096.3 missense, splice_region

Scores

1
18
Splicing: ADA: 0.00003023
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17
Variant links:
Genes affected
GTF2F1 (HGNC:4652): (general transcription factor IIF subunit 1) Enables several functions, including RNA polymerase II general transcription initiation factor activity; phosphatase activator activity; and promoter-specific chromatin binding activity. Involved in several processes, including positive regulation of transcription by RNA polymerase II; response to virus; and transcription initiation from RNA polymerase II promoter. Located in cell junction and nucleoplasm. Part of transcription factor TFIID complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.055540383).
BS2
High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GTF2F1NM_002096.3 linkc.1348G>A p.Gly450Ser missense_variant, splice_region_variant Exon 12 of 13 ENST00000394456.10 NP_002087.2 P35269
GTF2F1XM_047438710.1 linkc.1375G>A p.Gly459Ser missense_variant, splice_region_variant Exon 11 of 12 XP_047294666.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GTF2F1ENST00000394456.10 linkc.1348G>A p.Gly450Ser missense_variant, splice_region_variant Exon 12 of 13 1 NM_002096.3 ENSP00000377969.3 P35269
GTF2F1ENST00000593678.5 linkc.1096G>A p.Gly366Ser missense_variant, splice_region_variant Exon 9 of 10 2 ENSP00000469091.1 M0QXD6
GTF2F1ENST00000594213.5 linkn.715G>A splice_region_variant, non_coding_transcript_exon_variant Exon 5 of 6 3
GTF2F1ENST00000594965.1 linkn.666G>A splice_region_variant, non_coding_transcript_exon_variant Exon 5 of 6 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251418
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135894
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:
0.0000926
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461636
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1348G>A (p.G450S) alteration is located in exon 12 (coding exon 12) of the GTF2F1 gene. This alteration results from a G to A substitution at nucleotide position 1348, causing the glycine (G) at amino acid position 450 to be replaced by a serine (S). 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
0.072
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
12
DANN
Benign
0.92
DEOGEN2
Benign
0.057
T;T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.056
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.45
N;.
REVEL
Benign
0.056
Sift
Benign
0.63
T;.
Sift4G
Benign
0.97
T;T
Polyphen
0.0050
B;.
Vest4
0.16
MutPred
0.33
Gain of glycosylation at G450 (P = 0.036);.;
MVP
0.28
MPC
0.25
ClinPred
0.063
T
GERP RS
2.1
Varity_R
0.062
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000030
dbscSNV1_RF
Benign
0.022
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: rs756438444; hg19: chr19-6380585; COSMIC: COSV55532774; COSMIC: COSV55532774; API