chr22-19761162-A-G

Variant names:

• chr22-19761162-A-G
• rs1555895466
• NM_001379200.1:c.319A>G

Variant summary

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

The NM_001379200.1(TBX1):​c.319A>G​(p.Lys107Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000739 in 1,353,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19
• 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 2 ACMG points.

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

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.319A>G	p.Lys107Glu	missense	Exon 1 of 7	NP_001366129.1
	TBX1	NM_080647.1		c.292A>G	p.Lys98Glu	missense	Exon 3 of 9	NP_542378.1
	TBX1	NM_080646.2		c.292A>G	p.Lys98Glu	missense	Exon 3 of 9	NP_542377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.319A>G	p.Lys107Glu	missense	Exon 1 of 7	ENSP00000497003.1
	TBX1	ENST00000332710.8	TSL:1	c.292A>G	p.Lys98Glu	missense	Exon 3 of 9	ENSP00000331791.4
	TBX1	ENST00000329705.11	TSL:1	c.292A>G	p.Lys98Glu	missense	Exon 3 of 9	ENSP00000331176.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1353432 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 673518

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27476

American (AMR) AF: 0.00 AC: 0 AN: 36262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22306

East Asian (EAS) AF: 0.00 AC: 0 AN: 29798

South Asian (SAS) AF: 0.00 AC: 0 AN: 78328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052732

Other (OTH) AF: 0.00 AC: 0 AN: 53916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.090	D
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.41
Sift	Benign	0.047	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.27
MutPred		0.34		Loss of MoRF binding (P = 0.0045)
MVP		0.57
MPC		0.74
ClinPred		0.81	D
GERP RS		3.3
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.52
Mutation Taster		=80/20	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: rs1555895466; hg19: chr22-19748685;