ENST00000329705.11:c.*11C>T

Variant names:

• chr22-19779418-C-T
• rs72646973
• ENST00000329705.11:c.*11C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId is 504975.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 184 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329705.11. 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_080646.2		c.*11C>T		3_prime_UTR	Exon 9 of 9	NP_542377.1
	TBX1	NM_005992.1		c.1010-3495C>T		intron	N/A	NP_005983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000329705.11	TSL:1	c.*11C>T		3_prime_UTR	Exon 9 of 9	ENSP00000331176.7
	TBX1	ENST00000359500.7	TSL:1	c.1010-3495C>T		intron	N/A	ENSP00000352483.3

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

GnomAD2 exomes AF: 0.00131 AC: 330 AN: 251156 AF XY: 0.00132

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 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

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86250

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53408

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.00252 AC: 2806 AN: 1111988

Other (OTH) AF: 0.00166 AC: 100 AN: 60390

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

African (AFR) AF: 0.000361 AC: 15 AN: 41536

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.00127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.77
DANN	Benign	0.64
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

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