dbSNP rs875989847: GTF2E2:p.Asp187Tyr (chr8-30607141-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_002095.6(GTF2E2):c.559G>T(p.Asp187Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D187D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GTF2E2
NM_002095.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.85

Publications

5 publications found

Variant links:

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]

GTF2E2 Gene-Disease associations (from GenCC):

trichothiodystrophy 6, nonphotosensitive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GTF2E2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

PP5

Variant 8-30607141-C-A is Pathogenic according to our data. Variant chr8-30607141-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 225841.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2E2	NM_002095.6 link	c.559G>T	p.Asp187Tyr	missense_variant	Exon 6 of 8	ENST00000355904.9	NP_002086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2E2	ENST00000355904.9 link	c.559G>T	p.Asp187Tyr	missense_variant	Exon 6 of 8	1	NM_002095.6	ENSP00000348168.4		P29084

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

216910

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1189280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

602408

African (AFR)

AF:

0.00

AC:

AN:

26646

American (AMR)

AF:

0.00

AC:

AN:

35904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23390

East Asian (EAS)

AF:

0.00

AC:

AN:

37094

South Asian (SAS)

AF:

0.00

AC:

AN:

72242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5068

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

885624

Other (OTH)

AF:

0.00

AC:

AN:

50972

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Trichothiodystrophy 6, nonphotosensitive

Pathogenic:2

Apr 14, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

7.8

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.016

D;.

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.43

Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);

MVP

0.73

MPC

0.97

ClinPred

0.99

GERP RS

5.7

Varity_R

0.72

gMVP

0.72

Mutation Taster

=40/60

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over