rs13054377

Variant names:

• chr22-19766438-A-G
• rs13054377
• NM_001379200.1:c.1086A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379200.1(TBX1):​c.1086A>G​(p.Ala362Ala) 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
• Publications: 8 publications found

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]

TBX1 Gene-Disease associations (from GenCC):

• conotruncal heart malformations

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• DiGeorge syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• velocardiofacial syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 263355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379200.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_001379200.1	MANE Select	c.1086A>G	p.Ala362Ala	synonymous	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.1059A>G	p.Ala353Ala	synonymous	Exon 9 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.1009+436A>G		intron	N/A	NP_542377.1	O43435-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.1086A>G	p.Ala362Ala	synonymous	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.1059A>G	p.Ala353Ala	synonymous	Exon 9 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.1009+436A>G		intron	N/A	ENSP00000331176.7	O43435-1

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

GnomAD2 exomes AF: 0.0480 AC: 1827 AN: 38034 AF XY: 0.0449

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 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

African (AFR) AF: 0.196 AC: 4687 AN: 23944

American (AMR) AF: 0.0496 AC: 784 AN: 15792

Ashkenazi Jewish (ASJ) AF: 0.0581 AC: 1063 AN: 18304

East Asian (EAS) AF: 0.000155 AC: 4 AN: 25778

South Asian (SAS) AF: 0.0209 AC: 1110 AN: 53150

European-Finnish (FIN) AF: 0.0353 AC: 1020 AN: 28888

Middle Eastern (MID) AF: 0.0611 AC: 205 AN: 3354

European-Non Finnish (NFE) AF: 0.0675 AC: 65879 AN: 975320

Other (OTH) AF: 0.0694 AC: 3350 AN: 48278

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

African (AFR) AF: 0.187 AC: 7703 AN: 41300

American (AMR) AF: 0.0621 AC: 944 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 197 AN: 3458

East Asian (EAS) AF: 0.000588 AC: 3 AN: 5102

South Asian (SAS) AF: 0.0154 AC: 74 AN: 4818

European-Finnish (FIN) AF: 0.0311 AC: 320 AN: 10276

Middle Eastern (MID) AF: 0.0839 AC: 24 AN: 286

European-Non Finnish (NFE) AF: 0.0672 AC: 4548 AN: 67632

Other (OTH) AF: 0.0821 AC: 172 AN: 2096

Alfa AF: 0.0838 Hom.: 84

Bravo AF: 0.0991

Asia WGS AF: 0.0190 AC: 63 AN: 3382

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DiGeorge syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.9
DANN	Benign	0.24
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13054377; hg19: chr22-19753961;