NM_001379200.1:c.1244G>A

Variant names:

• chr22-19766596-G-A
• rs756543718
• NM_001379200.1:c.1244G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379200.1(TBX1):​c.1244G>A​(p.Gly415Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,488,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G415G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.868
• 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 Submitted by: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067380667).
• BP6: Variant 22-19766596-G-A is Benign according to our data. Variant chr22-19766596-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 455789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000264 (4/151284) while in subpopulation AMR AF = 0.000263 (4/15206). AF 95% confidence interval is 0.0000891. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 50 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.1244G>A	p.Gly415Asp	missense	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.1217G>A	p.Gly406Asp	missense	Exon 9 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.1009+594G>A		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.1244G>A	p.Gly415Asp	missense	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.1217G>A	p.Gly406Asp	missense	Exon 9 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.1009+594G>A		intron	N/A	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151284 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000327 AC: 38 AN: 116340 AF XY: 0.000239

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00181

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: 0.0000374 AC: 50 AN: 1337084 Hom.: 0 Cov.: 33 AF XY: 0.0000332 AC XY: 22 AN XY: 662266

African (AFR) AF: 0.00 AC: 0 AN: 27656

American (AMR) AF: 0.00151 AC: 48 AN: 31754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23086

East Asian (EAS) AF: 0.00 AC: 0 AN: 29028

South Asian (SAS) AF: 0.00 AC: 0 AN: 74436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4322

European-Non Finnish (NFE) AF: 9.46e-7 AC: 1 AN: 1057308

Other (OTH) AF: 0.0000182 AC: 1 AN: 54974

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151284 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73838

African (AFR) AF: 0.00 AC: 0 AN: 41302

American (AMR) AF: 0.000263 AC: 4 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67728

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000180 AC: 20

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.78	T
PhyloP100		0.87
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.17
Sift	Benign	0.065	T
Sift4G	Benign	0.63	T
Vest4		0.25
MutPred		0.30		Gain of solvent accessibility (P = 0.0638)
MVP		0.64
MPC		0.85
ClinPred		0.018	T
GERP RS		1.8
gMVP		0.26
Mutation Taster		=96/4	polymorphism

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: rs756543718; hg19: chr22-19754119;