7-74518158-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005685.4(GTF2IRD1):c.441C>G(p.Ala147=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000707 in 1,596,838 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: GTF2IRD1 NM_005685.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.63

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-74518158-C-G is Benign according to our data. Variant chr7-74518158-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 733730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 435 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2IRD1	NM_005685.4	c.441C>G	p.Ala147=	synonymous_variant	5/27	ENST00000424337.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2IRD1	ENST00000424337.7	c.441C>G	p.Ala147=	synonymous_variant	5/27	1	NM_005685.4	P1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000917 AC: 216 AN: 235520 Hom.: 1 AF XY: 0.000768 AC XY: 99 AN XY: 128938

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000476 AC: 687 AN: 1444500 Hom.: 1 Cov.: 31 AF XY: 0.000440 AC XY: 315 AN XY: 716058

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74492

Gnomad4 AFR AF: 0.00993

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00338

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	GTF2IRD1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

GTF2IRD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 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	-0.47
Cadd	Benign	8.7
Dann	Benign	0.59
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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: rs112098981; hg19: chr7-73932488; COSMIC: COSV56091776;