Genetic Variant GTF2IRD2B:p.Pro149Leu (chr7-75123223-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001003795.3(GTF2IRD2B):c.446C>T(p.Pro149Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000078 ( 1 hom., cov: 19)

Exomes 𝑓: 0.000070 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GTF2IRD2B
NM_001003795.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03

Variant links:

Genes affected

GTF2IRD2B (HGNC:33125): (GTF2I repeat domain containing 2B) This gene encodes a glycosylated phosphoprotein with a leucine zipper motif, two helix-loop-helix motifs (I repeats) that are similar to domains found in the TFII-I family of transcription factors, one CHARLIE8 transposable element-like sequence, and a BED zinc finger. This gene lies within a region that is deleted in Williams-Beuren syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

GTF2IRD2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2IRD2B	NM_001003795.3 link	c.446C>T	p.Pro149Leu	missense_variant	Exon 5 of 16	ENST00000472837.7	NP_001003795.1	Q6EKJ0-1
GTF2IRD2B	NM_001368302.1 link	c.932C>T	p.Pro311Leu	missense_variant	Exon 5 of 16		NP_001355231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2IRD2B	ENST00000472837.7 link	c.446C>T	p.Pro149Leu	missense_variant	Exon 5 of 16	1	NM_001003795.3	ENSP00000480524.1		Q6EKJ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000778

AC:

AN:

128516

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000863

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000971

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000118

AC:

AN:

202548

Hom.:

AF XY:

0.0000984

AC XY:

AN XY:

111782

show subpopulations

Gnomad AFR exome

AF:

0.0000759

Gnomad AMR exome

AF:

0.0000442

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00115

Gnomad SAS exome

AF:

0.0000842

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000703

AC:

AN:

1365596

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

677168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000348

Gnomad4 AMR exome

AF:

0.0000304

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00172

Gnomad4 SAS exome

AF:

0.0000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000181

Gnomad4 OTH exome

AF:

0.0000886

GnomAD4 genome

AF:

0.0000778

AC:

AN:

128594

Hom.:

Cov.:

AF XY:

0.0000652

AC XY:

AN XY:

61376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000865

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000971

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000970

Hom.:

ExAC

AF:

0.0000915

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446C>T (p.P149L) alteration is located in exon 5 (coding exon 4) of the GTF2IRD2B gene. This alteration results from a C to T substitution at nucleotide position 446, causing the proline (P) at amino acid position 149 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

3.2

M;.;.

PrimateAI

Uncertain

0.57

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.89

MutPred

0.94

Loss of disorder (P = 0.1205);Loss of disorder (P = 0.1205);Loss of disorder (P = 0.1205);

MVP

0.32

ClinPred

0.38

GERP RS

3.1

Varity_R

0.42

gMVP

0.47

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