Genetic Variant NM_005685.4:c.*220A>C (chr7-74602653-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005685.4(GTF2IRD1):c.*220A>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 432,214 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.038 ( 271 hom., cov: 32)

Exomes 𝑓: 0.047 ( 646 hom. )

Consequence

GTF2IRD1
NM_005685.4 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.574

Publications

7 publications found

Variant links:

Genes affected

GTF2IRD1 (HGNC:4661): (GTF2I repeat domain containing 1) The protein encoded by this gene contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene plays a role in craniofacial and cognitive development and mutations have been associated with Williams-Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7q11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

GTF2IRD1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

GTF2IRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2IRD1	NM_005685.4 link	c.*220A>C		downstream_gene_variant		ENST00000424337.7	NP_005676.3	Q9UHL9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2IRD1	ENST00000424337.7 link	c.*220A>C		downstream_gene_variant		1	NM_005685.4	ENSP00000408477.2		Q9UHL9-2

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

5743

AN:

151164

Hom.:

268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0423

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.0705

Gnomad FIN

AF:

0.0510

Gnomad MID

AF:

0.0195

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0431

GnomAD4 exome

AF:

0.0473

AC:

13283

AN:

280990

Hom.:

646

Cov.:

AF XY:

0.0486

AC XY:

7278

AN XY:

149840

show subpopulations

African (AFR)

AF:

0.00785

AC:

AN:

7898

American (AMR)

AF:

0.118

AC:

1385

AN:

11748

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

345

AN:

8886

East Asian (EAS)

AF:

0.171

AC:

3337

AN:

19494

South Asian (SAS)

AF:

0.0742

AC:

2092

AN:

28200

European-Finnish (FIN)

AF:

0.0367

AC:

539

AN:

14682

Middle Eastern (MID)

AF:

0.0373

AC:

AN:

1208

European-Non Finnish (NFE)

AF:

0.0278

AC:

4801

AN:

172792

Other (OTH)

AF:

0.0421

AC:

677

AN:

16082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

591

1182

1774

2365

2956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0381

AC:

5757

AN:

151224

Hom.:

271

Cov.:

AF XY:

0.0421

AC XY:

3108

AN XY:

73760

show subpopulations

African (AFR)

AF:

0.00602

AC:

248

AN:

41178

American (AMR)

AF:

0.102

AC:

1550

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.0423

AC:

147

AN:

3472

East Asian (EAS)

AF:

0.193

AC:

993

AN:

5150

South Asian (SAS)

AF:

0.0709

AC:

339

AN:

4784

European-Finnish (FIN)

AF:

0.0510

AC:

523

AN:

10258

Middle Eastern (MID)

AF:

0.0246

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0274

AC:

1860

AN:

67940

Other (OTH)

AF:

0.0433

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

267

534

800

1067

1334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0279

Hom.:

Bravo

AF:

0.0404

Asia WGS

AF:

0.124

AC:

431

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.1

(source)

DANN

Benign

0.51

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over