7-74518230-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_005685.4(GTF2IRD1):c.513A>G(p.Glu171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,610,598 control chromosomes in the GnomAD database, including 36,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5908 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30483 hom.)
• Consequence: GTF2IRD1 NM_005685.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-74518230-A-G is Benign according to our data. Variant chr7-74518230-A-G is described in ClinVar as [Benign]. Clinvar id is 3058945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.044 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2IRD1	NM_005685.4	c.513A>G	p.Glu171=	synonymous_variant	5/27	ENST00000424337.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2IRD1	ENST00000424337.7	c.513A>G	p.Glu171=	synonymous_variant	5/27	1	NM_005685.4	P1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38331 AN: 152082 Hom.: 5899 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.186 AC: 45717 AN: 245452 Hom.: 4941 AF XY: 0.182 AC XY: 24405 AN XY: 133762

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.0997

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.0928

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.198 AC: 288196 AN: 1458398 Hom.: 30483 Cov.: 33 AF XY: 0.196 AC XY: 142084 AN XY: 725388

Gnomad4 AFR exome AF: 0.445

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.0967

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.252 AC: 38378 AN: 152200 Hom.: 5908 Cov.: 32 AF XY: 0.244 AC XY: 18194 AN XY: 74418

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.0918

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0957

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.228

Alfa AF: 0.224 Hom.: 1790

Bravo AF: 0.268

Asia WGS AF: 0.177 AC: 615 AN: 3476

EpiCase AF: 0.206

EpiControl AF: 0.203

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GTF2IRD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.8
Dann	Benign	0.67

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

Other links and lift over

dbSNP: rs17851629; hg19: chr7-73932560; COSMIC: COSV56085193;