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7-74515421-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000455841.6(GTF2IRD1):c.342G>A(p.Ser114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,563,280 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S114S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0063 ( 43 hom. )

Consequence

GTF2IRD1
ENST00000455841.6 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.06
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-74515421-G-A is Benign according to our data. Variant chr7-74515421-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1176228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.06 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 683 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GTF2IRD1NM_005685.4 linkuse as main transcriptc.266-20G>A intron_variant ENST00000424337.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GTF2IRD1ENST00000424337.7 linkuse as main transcriptc.266-20G>A intron_variant 1 NM_005685.4 P1Q9UHL9-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00449
AC:
683
AN:
152184
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000772
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0127
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00700
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00434
AC:
764
AN:
175882
Hom.:
5
AF XY:
0.00443
AC XY:
419
AN XY:
94632
show subpopulations
Gnomad AFR exome
AF:
0.00105
Gnomad AMR exome
AF:
0.000603
Gnomad ASJ exome
AF:
0.00101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0118
Gnomad NFE exome
AF:
0.00746
Gnomad OTH exome
AF:
0.00329
GnomAD4 exome
AF:
0.00628
AC:
8865
AN:
1410978
Hom.:
43
Cov.:
32
AF XY:
0.00618
AC XY:
4311
AN XY:
698022
show subpopulations
Gnomad4 AFR exome
AF:
0.00103
Gnomad4 AMR exome
AF:
0.000591
Gnomad4 ASJ exome
AF:
0.00130
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000245
Gnomad4 FIN exome
AF:
0.0121
Gnomad4 NFE exome
AF:
0.00734
Gnomad4 OTH exome
AF:
0.00388
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00448
AC:
682
AN:
152302
Hom.:
3
Cov.:
32
AF XY:
0.00444
AC XY:
331
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000770
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0127
Gnomad4 NFE
AF:
0.00698
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00580
Hom.:
11
Bravo
AF:
0.00335

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024GTF2IRD1: BP4, BP7, BS2 -
GTF2IRD1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 08, 2019This 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
-0.88
Cadd
Benign
0.027
Dann
Benign
0.64
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs138159923; hg19: chr7-73929751; API