rs5748417

Variant names:

• chr22-19756987-T-C
• rs5748417
• ENST00000332710.8:c.-87+242T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000332710.8(TBX1):​c.-87+242T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 151,758 control chromosomes in the GnomAD database, including 9,036 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (9036 hom., cov: 31)
• Consequence: TBX1 ENST00000332710.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.78
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-87+242T>C		intron_variant	Intron 1 of 8		NP_542378.1
TBX1	NM_080646.2	c.-87+242T>C		intron_variant	Intron 1 of 8		NP_542377.1
TBX1	NM_005992.1	c.-87+242T>C		intron_variant	Intron 1 of 9		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-87+242T>C		intron_variant	Intron 1 of 8	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-87+242T>C		intron_variant	Intron 1 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-87+242T>C		intron_variant	Intron 1 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48276 AN: 151642 Hom.: 9027 Cov.: 31

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.281

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.318 AC: 48321 AN: 151758 Hom.: 9036 Cov.: 31 AF XY: 0.320 AC XY: 23725 AN XY: 74192

African (AFR) AF: 0.515 AC: 21282 AN: 41332

American (AMR) AF: 0.336 AC: 5127 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3468

East Asian (EAS) AF: 0.413 AC: 2116 AN: 5122

South Asian (SAS) AF: 0.236 AC: 1137 AN: 4814

European-Finnish (FIN) AF: 0.259 AC: 2728 AN: 10550

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.213 AC: 14454 AN: 67880

Other (OTH) AF: 0.283 AC: 597 AN: 2112

Alfa AF: 0.263 Hom.: 912

Bravo AF: 0.336

Asia WGS AF: 0.359 AC: 1243 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.016
DANN	Benign	0.42
PhyloP100		-3.8
PromoterAI		-0.0096	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs5748417; hg19: chr22-19744510;