NM_001379200.1:c.711+158T>C

Variant names:

• chr22-19764484-T-C
• rs41298826
• NM_001379200.1:c.711+158T>C

Variant summary

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

The NM_001379200.1(TBX1):​c.711+158T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,206 control chromosomes in the GnomAD database, including 3,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.19 (3538 hom., cov: 33)
• Consequence: TBX1 NM_001379200.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.428
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-19764484-T-C is Benign according to our data. Variant chr22-19764484-T-C is described in ClinVar as Benign. ClinVar VariationId is 1257183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.711+158T>C		intron_variant	Intron 3 of 6	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2	c.711+158T>C		intron_variant	Intron 3 of 6		NM_001379200.1	ENSP00000497003.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28204 AN: 152088 Hom.: 3539 Cov.: 33

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.206

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

GnomAD4 genome AF: 0.185 AC: 28203 AN: 152206 Hom.: 3538 Cov.: 33 AF XY: 0.188 AC XY: 13983 AN XY: 74404

African (AFR) AF: 0.0454 AC: 1888 AN: 41566

American (AMR) AF: 0.271 AC: 4147 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1112 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2486 AN: 5150

South Asian (SAS) AF: 0.237 AC: 1142 AN: 4826

European-Finnish (FIN) AF: 0.155 AC: 1643 AN: 10612

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15098 AN: 67964

Other (OTH) AF: 0.204 AC: 430 AN: 2112

Alfa AF: 0.211 Hom.: 608

Bravo AF: 0.187

Asia WGS AF: 0.312 AC: 1087 AN: 3476

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 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.3
DANN	Benign	0.43
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs41298826; hg19: chr22-19752007; COSMIC: COSV60354841; COSMIC: COSV60354841;