chr22-19757001-G-A

Variant names:

• chr22-19757001-G-A
• rs5748418
• ENST00000332710.8:c.-87+256G>A

Variant summary

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

The NM_080647.1(TBX1):​c.-87+256G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 151,924 control chromosomes in the GnomAD database, including 4,227 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 0.23 (4227 hom., cov: 32)
• Consequence: TBX1 NM_080647.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080647.1. 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_080647.1		c.-87+256G>A		intron	N/A	NP_542378.1
	TBX1	NM_080646.2		c.-87+256G>A		intron	N/A	NP_542377.1
	TBX1	NM_005992.1		c.-87+256G>A		intron	N/A	NP_005983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000332710.8	TSL:1	c.-87+256G>A		intron	N/A	ENSP00000331791.4
	TBX1	ENST00000329705.11	TSL:1	c.-87+256G>A		intron	N/A	ENSP00000331176.7
	TBX1	ENST00000359500.7	TSL:1	c.-87+256G>A		intron	N/A	ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35282 AN: 151808 Hom.: 4227 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.232 AC: 35295 AN: 151924 Hom.: 4227 Cov.: 32 AF XY: 0.236 AC XY: 17527 AN XY: 74266

African (AFR) AF: 0.223 AC: 9244 AN: 41440

American (AMR) AF: 0.300 AC: 4577 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3470

East Asian (EAS) AF: 0.411 AC: 2113 AN: 5140

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4816

European-Finnish (FIN) AF: 0.258 AC: 2727 AN: 10558

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14178 AN: 67910

Other (OTH) AF: 0.224 AC: 473 AN: 2112

Alfa AF: 0.219 Hom.: 452

Bravo AF: 0.239

Asia WGS AF: 0.336 AC: 1163 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.85
PhyloP100		-1.2
PromoterAI		-0.11	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: rs5748418; hg19: chr22-19744524;