Variant 15-59642217-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004492.3(GTF2A2):c.223G>T(p.Val75Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GTF2A2
NM_004492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55

Variant links:

Genes affected

GTF2A2 (HGNC:4647): (general transcription factor IIA subunit 2) Accurate transcription initiation on TATA-containing class II genes involves the ordered assembly of RNA polymerase II (POLR2A; MIM 180660) and the general initiation factors TFIIA, TFIIB (MIM 189963), TFIID (MIM 313650), TFIIE (MIM 189962), TFIIF (MIM 189968), TFIIG/TFIIJ, and TFIIH (MIM 189972). The first step involves recognition of the TATA element by the TATA-binding subunit (TBP; MIM 600075) and may be regulated by TFIIA, a factor that interacts with both TBP and a TBP-associated factor (TAF; MIM 600475) in TFIID. TFIIA has 2 subunits (43 and 12 kD) in yeast and 3 subunits in higher eukaryotes. In HeLa extracts, it consists of a 35-kD alpha subunit and a 19-kD beta subunit encoded by the N- and C-terminal regions of GTF2A1 (MIM 600520), respectively, and a 12-kD gamma subunit encoded by GTF2A2 (DeJong et al., 1995 [PubMed 7724559]).[supplied by OMIM, Mar 2008]

GTF2A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36817145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GTF2A2	NM_004492.3 linkuse as main transcript	c.223G>T	p.Val75Leu	missense_variant	4/5	ENST00000396060.7
GTF2A2	NM_001320929.2 linkuse as main transcript	c.223G>T	p.Val75Leu	missense_variant	4/5
GTF2A2	NM_001320930.2 linkuse as main transcript	c.223G>T	p.Val75Leu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2A2	ENST00000396060.7 linkuse as main transcript	c.223G>T	p.Val75Leu	missense_variant	4/5	1	NM_004492.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134774

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.223G>T (p.V75L) alteration is located in exon 4 (coding exon 3) of the GTF2A2 gene. This alteration results from a G to T substitution at nucleotide position 223, causing the valine (V) at amino acid position 75 to be replaced by a leucine (L). 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

0.74

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;T;T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.010

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.32

N;N;N;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.91

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.63

T;T;T;T;T

Sift4G

Benign

0.53

T;T;T;T;.

Polyphen

0.0020

B;B;B;.;.

Vest4

0.77

MutPred

0.57

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;

MVP

0.19

MPC

0.41

ClinPred

0.44

GERP RS

5.5

Varity_R

0.44

gMVP

0.59

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over