rs139776757

chr22-19763274-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001379200.1(TBX1):c.471C>T(p.Phe157=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,614,176 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (18 hom.)
• Consequence: TBX1 NM_001379200.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.49

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 22-19763274-C-T is Benign according to our data. Variant chr22-19763274-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 455792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19763274-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (453/152358) while in subpopulation NFE AF= 0.00537 (365/68032). AF 95% confidence interval is 0.00491. There are 1 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 453 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_001379200.1	c.471C>T	p.Phe157=	synonymous_variant	2/7	ENST00000649276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000649276.2	c.471C>T	p.Phe157=	synonymous_variant	2/7		NM_001379200.1	A2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00277 AC: 696 AN: 251386 Hom.: 3 AF XY: 0.00290 AC XY: 394 AN XY: 135896

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00496

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00437 AC: 6381 AN: 1461818 Hom.: 18 Cov.: 31 AF XY: 0.00421 AC XY: 3065 AN XY: 727210

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00275 AC XY: 205 AN XY: 74506

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00431 Hom.: 1

Bravo AF: 0.00281

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TBX1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 31, 2024

- -

DiGeorge syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs139776757; hg19: chr22-19750797; COSMIC: COSV60353517; COSMIC: COSV60353517;