NM_001379200.1:c.1380T>G

Variant names:

• chr22-19766732-T-G
• rs367711718
• NM_001379200.1:c.1380T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001379200.1(TBX1):​c.1380T>G​(p.His460Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,541,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H460R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0100
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21027526).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000596 (9/150886) while in subpopulation SAS AF = 0.000208 (1/4804). AF 95% confidence interval is 0.0000327. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 9 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.1380T>G	p.His460Gln	missense	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.1353T>G	p.His451Gln	missense	Exon 9 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.1009+730T>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.1380T>G	p.His460Gln	missense	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.1353T>G	p.His451Gln	missense	Exon 9 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.1009+730T>G		intron	N/A	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes AF: 0.0000597 AC: 9 AN: 150780 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000235 AC: 4 AN: 170270 AF XY: 0.0000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 76 AN: 1390582 Hom.: 0 Cov.: 33 AF XY: 0.0000607 AC XY: 42 AN XY: 691520

African (AFR) AF: 0.000104 AC: 3 AN: 28736

American (AMR) AF: 0.0000256 AC: 1 AN: 38992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24194

East Asian (EAS) AF: 0.000120 AC: 4 AN: 33240

South Asian (SAS) AF: 0.000174 AC: 14 AN: 80660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.0000488 AC: 53 AN: 1086284

Other (OTH) AF: 0.0000174 AC: 1 AN: 57332

GnomAD4 genome AF: 0.0000596 AC: 9 AN: 150886 Hom.: 0 Cov.: 33 AF XY: 0.0000678 AC XY: 5 AN XY: 73728

African (AFR) AF: 0.0000976 AC: 4 AN: 40990

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5028

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67692

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000269 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	DiGeorge syndrome (1)
-	1	-	DiGeorge syndrome;C0039685:Tetralogy of Fallot;C0220704:Velocardiofacial syndrome;C1857586:Conotruncal heart malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.69	T
PhyloP100		0.010
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.31
Sift	Benign	0.035	D
Sift4G	Benign	0.22	T
Vest4		0.34
MutPred		0.092		Loss of glycosylation at P452 (P = 0.0977)
MVP		0.59
MPC		1.1
ClinPred		0.83	D
GERP RS		1.7
gMVP		0.36
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367711718; hg19: chr22-19754255;