chr22-19766398-A-C

Variant names:

• chr22-19766398-A-C
• rs751917634
• NM_001379200.1:c.1046A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379200.1(TBX1):​c.1046A>C​(p.Glu349Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E349K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0750
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2724761).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_001379200.1	MANE Select	c.1046A>C	p.Glu349Ala	missense	Exon 7 of 7	NP_001366129.1
	TBX1	NM_080647.1		c.1019A>C	p.Glu340Ala	missense	Exon 9 of 9	NP_542378.1
	TBX1	NM_080646.2		c.1009+396A>C		intron	N/A	NP_542377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.1046A>C	p.Glu349Ala	missense	Exon 7 of 7	ENSP00000497003.1
	TBX1	ENST00000332710.8	TSL:1	c.1019A>C	p.Glu340Ala	missense	Exon 9 of 9	ENSP00000331791.4
	TBX1	ENST00000329705.11	TSL:1	c.1009+396A>C		intron	N/A	ENSP00000331176.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.93
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.69	T
PhyloP100		0.075
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.26
Sift	Benign	0.15	T
Sift4G	Benign	0.075	T
Vest4		0.29
MutPred		0.27		Gain of helix (P = 0.0854)
MVP		0.75
MPC		0.58
ClinPred		0.86	D
GERP RS		2.2
gMVP		0.36
Mutation Taster		=82/18	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: rs751917634; hg19: chr22-19753921;