Genetic Variant GTF2IRD2:p.Ser188Asn (chr7-74822435-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173537.5(GTF2IRD2):c.563G>A(p.Ser188Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 14)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GTF2IRD2
NM_173537.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.143

Variant links:

Genes affected

GTF2IRD2 (HGNC:30775): (GTF2I repeat domain containing 2) This gene is one of several closely related genes on chromosome 7 encoding proteins containing helix-loop-helix motifs. These proteins may function as regulators of transcription. The encoded protein is unique in that its C-terminus is derived from CHARLIE8 transposable element sequence. This gene is located in a region of chromosome 7 that is deleted in Williams-Beuren syndrome, and loss of this locus may contribute to the cognitive phenotypes observed in this disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

GTF2IRD2 links:

ENSG00000289346 (HGNC:):

ENSG00000289346 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04446733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2IRD2	NM_173537.5 link	c.563G>A	p.Ser188Asn	missense_variant	Exon 6 of 16	ENST00000451013.7	NP_775808.4	Q86UP8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GTF2IRD2	ENST00000451013.7 link	c.563G>A	p.Ser188Asn	missense_variant	Exon 6 of 16	1	NM_173537.5	ENSP00000406723.3	Q86UP8-1
ENSG00000289346	ENST00000625377.3 link	c.563G>A	p.Ser188Asn	missense_variant	Exon 13 of 23	5		ENSP00000486581.2	A0A0D9SF80
GTF2IRD2	ENST00000651129.1 link	c.1049G>A	p.Ser350Asn	missense_variant	Exon 7 of 17			ENSP00000498563.1	A0A494C0I1
GTF2IRD2	ENST00000619775.1 link	n.906G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

108190

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000414

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:

0.0000176

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

732948

Hom.:

Cov.:

AF XY:

0.00000258

AC XY:

AN XY:

387482

show subpopulations

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:

0.00000425

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000185

AC:

AN:

108190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50218

show subpopulations

Gnomad4 AFR

AF:

0.0000414

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:

0.0000176

Gnomad4 OTH

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

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563G>A (p.S188N) alteration is located in exon 6 (coding exon 5) of the GTF2IRD2 gene. This alteration results from a G to A substitution at nucleotide position 563, causing the serine (S) at amino acid position 188 to be replaced by an asparagine (N). 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

0.067

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.2

DANN

Benign

0.90

DEOGEN2

Benign

0.0062

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;.

PrimateAI

Benign

0.39

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;.

Vest4

0.099

MutPred

0.18

Loss of glycosylation at S188 (P = 0.0586);Loss of glycosylation at S188 (P = 0.0586);

MVP

0.014

ClinPred

0.33

GERP RS

-0.20

Varity_R

0.036

gMVP

0.038

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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