rs72646973

chr22-19779418-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000329705.11(TBX1):c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: TBX1 ENST00000329705.11 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.11

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-19779418-C-T is Benign according to our data. Variant chr22-19779418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504975.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr22-19779418-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152230) while in subpopulation NFE AF= 0.00228 (155/68016). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_080646.2	c.*11C>T		3_prime_UTR_variant	9/9
TBX1	NM_005992.1	c.1010-3495C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000329705.11	c.*11C>T		3_prime_UTR_variant	9/9	1		A2
TBX1	ENST00000359500.7	c.1010-3495C>T		intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152112 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00131 AC: 330 AN: 251156 Hom.: 2 AF XY: 0.00132 AC XY: 179 AN XY: 135836

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00207 AC: 3025 AN: 1461832 Hom.: 2 Cov.: 33 AF XY: 0.00197 AC XY: 1435 AN XY: 727222

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152230 Hom.: 1 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74420

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.00127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 27, 2016

Variant classified as Uncertain Significance - Favor Benign. The c.*11C>T varian t in TBX1 has been reported in 1 individual with TOF and his presumably unaffect ed mother. The patient also carried variants in other genes associated with cong enital heart defects (Topf 2014). This variant has been identified in 0.2% (133/ 44688) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs72646973). Although it has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . In summary, while the clinical significance of the c.*11C>T variant is uncerta in, its frequency suggest that it is more likely to be benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

TBX1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.77
Dann	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72646973; hg19: chr22-19766941; COSMIC: COSV61549749; COSMIC: COSV61549749;