rs72646967

chr22-19766568-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379200.1(TBX1):c.1216A>C(p.Asn406His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,441,986 control chromosomes in the GnomAD database, including 37,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N406S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (3490 hom., cov: 32)
  • Exomes 𝑓: 0.22 (33925 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002857238).
• BP6: Variant 22-19766568-A-C is Benign according to our data. Variant chr22-19766568-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 263351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19766568-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_001379200.1	c.1216A>C	p.Asn406His	missense_variant	7/7	ENST00000649276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000649276.2	c.1216A>C	p.Asn406His	missense_variant	7/7		NM_001379200.1	A2
TBX1	ENST00000332710.8	c.1189A>C	p.Asn397His	missense_variant	9/9	1		P2
TBX1	ENST00000329705.11	c.1009+566A>C		intron_variant		1		A2
TBX1	ENST00000359500.7	c.1009+566A>C		intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 27927 AN: 150614 Hom.: 3492 Cov.: 32

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.251 AC: 20007 AN: 79850 Hom.: 2801 AF XY: 0.244 AC XY: 11261 AN XY: 46122

Gnomad AFR exome AF: 0.0373

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.483

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.221 AC: 285760 AN: 1291264 Hom.: 33925 Cov.: 33 AF XY: 0.222 AC XY: 141502 AN XY: 636556

Gnomad4 AFR exome AF: 0.0354

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.185 AC: 27922 AN: 150722 Hom.: 3490 Cov.: 32 AF XY: 0.188 AC XY: 13808 AN XY: 73626

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.204

Alfa AF: 0.211 Hom.: 640

Bravo AF: 0.186

TwinsUK AF: 0.217 AC: 806

ALSPAC AF: 0.210 AC: 810

ESP6500AA AF: 0.0304 AC: 75

ESP6500EA AF: 0.150 AC: 825

ExAC AF: 0.143 AC: 12700

Asia WGS AF: 0.300 AC: 1006 AN: 3342

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

DiGeorge syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

This alteration is classified as 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_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.87
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.91	N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Vest4		0.072
MPC		0.55
ClinPred		0.0012	T
GERP RS		2.9
gMVP		0.27

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: rs72646967; hg19: chr22-19754091; COSMIC: COSV60354232; COSMIC: COSV60354232;