rs72646953

Variant names:

• chr22-19761167-G-A
• rs72646953
• NM_001379200.1:c.324G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19761167-G-A
• chr22-19761167-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001379200.1(TBX1):​c.324G>A​(p.Ala108Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,520,306 control chromosomes in the GnomAD database, including 831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (48 hom., cov: 32)
  • Exomes 𝑓: 0.032 (783 hom.)
• Consequence: TBX1 NM_001379200.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.342
• Publications: 12 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-19761167-G-A is Benign according to our data. Variant chr22-19761167-G-A is described in ClinVar as Benign. ClinVar VariationId is 263555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (3059/151046) while in subpopulation NFE AF = 0.031 (2102/67710). AF 95% confidence interval is 0.0299. There are 48 homozygotes in GnomAd4. There are 1439 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3059 AD gene.

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.324G>A	p.Ala108Ala	synonymous	Exon 1 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.297G>A	p.Ala99Ala	synonymous	Exon 3 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.297G>A	p.Ala99Ala	synonymous	Exon 3 of 9	NP_542377.1	O43435-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.324G>A	p.Ala108Ala	synonymous	Exon 1 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.297G>A	p.Ala99Ala	synonymous	Exon 3 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.297G>A	p.Ala99Ala	synonymous	Exon 3 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3061 AN: 150940 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0231 AC: 4470 AN: 193580 AF XY: 0.0231

Gnomad AFR exome AF: 0.00569

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0315 AC: 43132 AN: 1369260 Hom.: 783 Cov.: 31 AF XY: 0.0307 AC XY: 20944 AN XY: 681282

African (AFR) AF: 0.00437 AC: 122 AN: 27942

American (AMR) AF: 0.0258 AC: 952 AN: 36914

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 410 AN: 22856

East Asian (EAS) AF: 0.000129 AC: 4 AN: 30924

South Asian (SAS) AF: 0.0174 AC: 1375 AN: 79000

European-Finnish (FIN) AF: 0.0212 AC: 1061 AN: 50142

Middle Eastern (MID) AF: 0.00511 AC: 21 AN: 4110

European-Non Finnish (NFE) AF: 0.0354 AC: 37613 AN: 1062418

Other (OTH) AF: 0.0286 AC: 1574 AN: 54954

GnomAD4 genome AF: 0.0203 AC: 3059 AN: 151046 Hom.: 48 Cov.: 32 AF XY: 0.0195 AC XY: 1439 AN XY: 73786

African (AFR) AF: 0.00604 AC: 250 AN: 41396

American (AMR) AF: 0.0210 AC: 318 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4820

European-Finnish (FIN) AF: 0.0222 AC: 224 AN: 10080

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0310 AC: 2102 AN: 67710

Other (OTH) AF: 0.0185 AC: 39 AN: 2104

Alfa AF: 0.0202 Hom.: 33

Bravo AF: 0.0200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DiGeorge syndrome (1)
-	-	1	TBX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		0.34
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=94/6	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: rs72646953; hg19: chr22-19748690; COSMIC: COSV107350037; COSMIC: COSV107350037;