Variant 7-74698963-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_032999.4(GTF2I):c.241G>C(p.Val81Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,347,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GTF2I
NM_032999.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

GTF2I (HGNC:4659): (general transcription factor IIi) This gene encodes a phosphoprotein containing six characteristic repeat motifs. The encoded protein binds to the initiator element (Inr) and E-box element in promoters and functions as a regulator of transcription. This locus, along with several other neighboring genes, is deleted in Williams-Beuren syndrome. There are many closely related genes and pseudogenes for this gene on chromosome 7. This gene also has pseudogenes on chromosomes 9, 13, and 21. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Jul 2013]

GTF2I links:

GTF2I-AS1 (HGNC:):

GTF2I-AS1 links:

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=0.015278697).

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2I	NM_032999.4 linkuse as main transcript	c.241G>C	p.Val81Leu	missense_variant, splice_region_variant	4/35	ENST00000573035.6	NP_127492.1	P78347-1X5DR09Q499G6A8K9W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2I	ENST00000573035.6 linkuse as main transcript	c.241G>C	p.Val81Leu	missense_variant, splice_region_variant	4/35	1	NM_032999.4	ENSP00000460070.1		P78347-1

Frequencies

GnomAD3 genomes

AF:

0.000389

AC:

AN:

151688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000733

AC:

AN:

122748

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

67848

show subpopulations

Gnomad AFR exome

AF:

0.00112

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1195354

Hom.:

Cov.:

AF XY:

0.00000676

AC XY:

AN XY:

591530

show subpopulations

Gnomad4 AFR exome

AF:

0.000563

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:

0.0000409

GnomAD4 genome

AF:

0.000389

AC:

AN:

151806

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.00138

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000476

Bravo

AF:

0.000438

ESP6500AA

AF:

0.000914

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000133

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

Sep 03, 2024

The c.241G>C (p.V81L) alteration is located in exon 4 (coding exon 3) of the GTF2I gene. This alteration results from a G to C substitution at nucleotide position 241, causing the valine (V) at amino acid position 81 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

Benign

0.31

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.39

T;.;.;.;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.015

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

L;L;L;L;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

.;.;.;.;N;N

REVEL

Benign

0.045

Sift

Benign

0.38

.;.;.;.;T;T

Sift4G

Benign

0.41

T;T;T;T;T;T

Polyphen

0.96

D;P;B;B;.;.

Vest4

0.30

MVP

0.49

ClinPred

0.094

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.29

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

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