rs41298840

chr22-19765926-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379200.1(TBX1):c.960A>G(p.Ala320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,527,280 control chromosomes in the GnomAD database, including 39,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3524 hom., cov: 33)
  • Exomes 𝑓: 0.22 (36323 hom.)
• Consequence: TBX1 NM_001379200.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.830

Genes affected

TBX1 (HGNC:11592): (T-box transcription factor 1) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 22-19765926-A-G is Benign according to our data. Variant chr22-19765926-A-G is described in ClinVar as [Benign]. Clinvar id is 263444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19765926-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_001379200.1	c.960A>G	p.Ala320=	synonymous_variant	6/7	ENST00000649276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000649276.2	c.960A>G	p.Ala320=	synonymous_variant	6/7		NM_001379200.1	A2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28121 AN: 151480 Hom.: 3527 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.230 AC: 28609 AN: 124464 Hom.: 3906 AF XY: 0.229 AC XY: 15549 AN XY: 67972

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.221 AC: 304257 AN: 1375688 Hom.: 36323 Cov.: 34 AF XY: 0.222 AC XY: 150769 AN XY: 678254

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.219

GnomAD4 genome AF: 0.185 AC: 28114 AN: 151592 Hom.: 3524 Cov.: 33 AF XY: 0.188 AC XY: 13919 AN XY: 74074

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.483

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.202

Alfa AF: 0.213 Hom.: 808

Bravo AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

DiGeorge syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	10
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs41298840; hg19: chr22-19753449; COSMIC: COSV60353728; COSMIC: COSV60353728;