8-30580367-C-T

Position:

• chr8-30580367-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002095.6(GTF2E2):​c.673G>A​(p.Val225Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,762 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: 6.9e-7 (0 hom.)
• Consequence: GTF2E2 NM_002095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

Genes affected

GTF2E2 (HGNC:4651): (general transcription factor IIE subunit 2) The general transcription factor IIE (TFIIE) is part of the RNA polymerase II transcription initiation complex, recruiting TFIIH and being essential for promoter clearance by RNA polymerase II. TFIIE is a heterodimer (and sometimes heterotetramer) of alpha and beta subunits. The protein encoded by this gene represents the beta subunit of TFIIE. [provided by RefSeq, Jan 2017]

ACMG classification

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=0.36001194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2E2	NM_002095.6	c.673G>A	p.Val225Ile	missense_variant	7/8	ENST00000355904.9	NP_002086.1
GTF2E2	XM_017013363.2	c.673G>A	p.Val225Ile	missense_variant	7/8		XP_016868852.1
GTF2E2	XM_017013364.2	c.673G>A	p.Val225Ile	missense_variant	7/8		XP_016868853.1
GTF2E2	XM_024447138.2	c.673G>A	p.Val225Ile	missense_variant	7/8		XP_024302906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2E2	ENST00000355904.9	c.673G>A	p.Val225Ile	missense_variant	7/8	1	NM_002095.6	ENSP00000348168.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440762 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718120

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: 9.15e-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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GTF2E2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 225 of the GTF2E2 protein (p.Val225Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.93	P
Vest4		0.36
MutPred		0.39		Loss of disorder (P = 0.1927);
MVP		0.58
MPC		0.58
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-30437884;