ENST00000329705.11:c.*121G>T

Variant names:

• chr22-19779528-G-T
• rs5746826
• ENST00000329705.11:c.*121G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000329705.11(TBX1):​c.*121G>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 0.468 in 1,532,480 control chromosomes in the GnomAD database, including 173,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22269 hom., cov: 33)
  • Exomes 𝑓: 0.46 (151340 hom.)
• Consequence: TBX1 ENST00000329705.11 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.952
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-19779528-G-T is Benign according to our data. Variant chr22-19779528-G-T is described in ClinVar as Benign. ClinVar VariationId is 1226089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

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.*121G>T		3_prime_UTR	Exon 9 of 9	NP_542377.1
	TBX1	NM_005992.1		c.1010-3385G>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.*121G>T		3_prime_UTR	Exon 9 of 9	ENSP00000331176.7
	TBX1	ENST00000359500.7	TSL:1	c.1010-3385G>T		intron	N/A	ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80326 AN: 151976 Hom.: 22225 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.544

GnomAD4 exome AF: 0.462 AC: 637488 AN: 1380386 Hom.: 151340 Cov.: 30 AF XY: 0.466 AC XY: 317097 AN XY: 679986

African (AFR) AF: 0.687 AC: 21359 AN: 31092

American (AMR) AF: 0.615 AC: 21437 AN: 34840

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 15240 AN: 24818

East Asian (EAS) AF: 0.574 AC: 20584 AN: 35868

South Asian (SAS) AF: 0.594 AC: 46105 AN: 77678

European-Finnish (FIN) AF: 0.353 AC: 16113 AN: 45696

Middle Eastern (MID) AF: 0.581 AC: 2334 AN: 4014

European-Non Finnish (NFE) AF: 0.436 AC: 466246 AN: 1069174

Other (OTH) AF: 0.491 AC: 28070 AN: 57206

GnomAD4 genome AF: 0.529 AC: 80426 AN: 152094 Hom.: 22269 Cov.: 33 AF XY: 0.529 AC XY: 39304 AN XY: 74356

African (AFR) AF: 0.674 AC: 27961 AN: 41492

American (AMR) AF: 0.595 AC: 9099 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2157 AN: 3472

East Asian (EAS) AF: 0.589 AC: 3050 AN: 5174

South Asian (SAS) AF: 0.599 AC: 2884 AN: 4816

European-Finnish (FIN) AF: 0.346 AC: 3666 AN: 10582

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29756 AN: 67944

Other (OTH) AF: 0.541 AC: 1144 AN: 2114

Alfa AF: 0.475 Hom.: 56797

Bravo AF: 0.552

Asia WGS AF: 0.564 AC: 1961 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.15
DANN	Benign	0.41
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs5746826; hg19: chr22-19767051;