22-19766404-G-C

Variant names:

• chr22-19766404-G-C
• rs549715785
• NM_001379200.1:c.1052G>C
• TBX1 p.Arg351Pro

Variant summary

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

The NM_001379200.1(TBX1):​c.1052G>C​(p.Arg351Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000084 in 1,190,496 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R351Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_001379200.1	MANE Select	c.1052G>C	p.Arg351Pro	missense	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.1025G>C	p.Arg342Pro	missense	Exon 9 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.1009+402G>C		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.1052G>C	p.Arg351Pro	missense	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.1025G>C	p.Arg342Pro	missense	Exon 9 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.1009+402G>C		intron	N/A	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.40e-7 AC: 1 AN: 1190496 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 582000

African (AFR) AF: 0.00 AC: 0 AN: 23564

American (AMR) AF: 0.00 AC: 0 AN: 14068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17668

East Asian (EAS) AF: 0.0000389 AC: 1 AN: 25702

South Asian (SAS) AF: 0.00 AC: 0 AN: 51990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 978196

Other (OTH) AF: 0.00 AC: 0 AN: 47618

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.51	T
PhyloP100		1.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.12	T
Sift4G	Benign	0.30	T
gMVP		0.45
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs549715785;

hg19: chr22-19753927;