chr22-19766613-C-A

Variant names:

• chr22-19766613-C-A
• rs985907694
• NM_001379200.1:c.1261C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001379200.1(TBX1):​c.1261C>A​(p.His421Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H421H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.1261C>A	p.His421Asn	missense_variant	Exon 7 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2	c.1261C>A	p.His421Asn	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1
TBX1	ENST00000332710.8	c.1234C>A	p.His412Asn	missense_variant	Exon 9 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.1009+611C>A		intron_variant	Intron 8 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.1009+611C>A		intron_variant	Intron 8 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 153756 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1375038 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 682858

African (AFR) AF: 0.00 AC: 0 AN: 28792

American (AMR) AF: 0.00 AC: 0 AN: 37294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23926

East Asian (EAS) AF: 0.00 AC: 0 AN: 31806

South Asian (SAS) AF: 0.00 AC: 0 AN: 78548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077070

Other (OTH) AF: 0.00 AC: 0 AN: 56678

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DiGeorge syndrome Uncertain:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 412 of the TBX1 protein (p.His412Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TBX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578044). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	-0.053	T
PhyloP100		2.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.85	N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D;.
Sift4G	Benign	0.15	T;.
Vest4		0.46
MutPred		0.29		Gain of catalytic residue at H412 (P = 0.0634);.;
MVP		0.80
MPC		1.5
ClinPred		0.97	D
GERP RS		3.5
gMVP		0.36
Mutation Taster		=46/54	disease causing

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: rs985907694; hg19: chr22-19754136;