rs13054377

Positions:

• chr22-19766438-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.1086A>G​(p.Ala362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,343,886 control chromosomes in the GnomAD database, including 3,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (926 hom., cov: 33)
  • Exomes 𝑓: 0.065 (2973 hom.)
• Consequence: TBX1 NM_001379200.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.53

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=-0.75).
• BP6: Variant 22-19766438-A-G is Benign according to our data. Variant chr22-19766438-A-G is described in ClinVar as [Benign]. Clinvar id is 263355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19766438-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_001379200.1	c.1086A>G	p.Ala362=	synonymous_variant	7/7	ENST00000649276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000649276.2	c.1086A>G	p.Ala362=	synonymous_variant	7/7		NM_001379200.1	A2
TBX1	ENST00000332710.8	c.1059A>G	p.Ala353=	synonymous_variant	9/9	1		P2
TBX1	ENST00000329705.11	c.1009+436A>G		intron_variant		1		A2
TBX1	ENST00000359500.7	c.1009+436A>G		intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14080 AN: 150968 Hom.: 925 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0622

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0784

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0829

GnomAD3 exomes AF: 0.0480 AC: 1827 AN: 38034 Hom.: 66 AF XY: 0.0449 AC XY: 1014 AN XY: 22580

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0655 AC: 78102 AN: 1192808 Hom.: 2973 Cov.: 22 AF XY: 0.0638 AC XY: 37286 AN XY: 584386

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.0496

Gnomad4 ASJ exome AF: 0.0581

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0675

Gnomad4 OTH exome AF: 0.0694

GnomAD4 genome AF: 0.0932 AC: 14085 AN: 151078 Hom.: 926 Cov.: 33 AF XY: 0.0891 AC XY: 6582 AN XY: 73846

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0621

Gnomad4 ASJ AF: 0.0570

Gnomad4 EAS AF: 0.000588

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0672

Gnomad4 OTH AF: 0.0821

Alfa AF: 0.0838 Hom.: 84

Bravo AF: 0.0991

Asia WGS AF: 0.0190 AC: 63 AN: 3382

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
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	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DiGeorge syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 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	-0.75
CADD	Benign	1.9
DANN	Benign	0.24

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: rs13054377; hg19: chr22-19753961;