Variant 11-18351968-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000265963.9(GTF2H1):c.1141A>G(p.Arg381Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000714 in 1,399,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GTF2H1
ENST00000265963.9 missense, splice_region

Scores

Splicing: ADA: 0.9928

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.31

Variant links:

Genes affected

GTF2H1 (HGNC:4655): (general transcription factor IIH subunit 1) Enables thyroid hormone receptor binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor TFIIH core complex and transcription factor TFIIH holo complex. [provided by Alliance of Genome Resources, Apr 2022]

GTF2H1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2H1	NM_005316.4 linkuse as main transcript	c.1141A>G	p.Arg381Gly	missense_variant, splice_region_variant	10/15	ENST00000265963.9	NP_005307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2H1	ENST00000265963.9 linkuse as main transcript	c.1141A>G	p.Arg381Gly	missense_variant, splice_region_variant	10/15	1	NM_005316.4	ENSP00000265963	P1	P32780-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700532

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

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

Oct 12, 2021

The c.1141A>G (p.R381G) alteration is located in exon 11 (coding exon 9) of the GTF2H1 gene. This alteration results from a A to G substitution at nucleotide position 1141, causing the arginine (R) at amino acid position 381 to be replaced by a glycine (G). 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

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.9

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;T

Polyphen

0.97

D;.;D;.

Vest4

0.89

MutPred

0.50

Loss of MoRF binding (P = 0.0272);.;Loss of MoRF binding (P = 0.0272);.;

MVP

0.74

MPC

0.34

ClinPred

0.99

GERP RS

5.5

Varity_R

0.85

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

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.

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