rs1001921296

Variant names:

• chr22-19766434-C-A
• rs1001921296
• NM_001379200.1:c.1082C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19766434-C-A
• chr22-19766434-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379200.1(TBX1):​c.1082C>A​(p.Pro361Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,198,006 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. 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. P361L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20822075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.1082C>A	p.Pro361Gln	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.1082C>A	p.Pro361Gln	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000167 AC: 2 AN: 1198006 Hom.: 0 Cov.: 23 AF XY: 0.00000170 AC XY: 1 AN XY: 586930

African (AFR) AF: 0.00 AC: 0 AN: 24028

American (AMR) AF: 0.00 AC: 0 AN: 16602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18518

East Asian (EAS) AF: 0.00 AC: 0 AN: 25784

South Asian (SAS) AF: 0.00 AC: 0 AN: 54044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3368

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 978166

Other (OTH) AF: 0.00 AC: 0 AN: 48466

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.33	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.74	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.37	T;.
Vest4		0.16
MutPred		0.26		Gain of solvent accessibility (P = 0.0648);.;
MVP		0.81
MPC		0.56
ClinPred		0.13	T
GERP RS		1.1
gMVP		0.27
Mutation Taster		=52/48	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: rs1001921296; hg19: chr22-19753957;