rs4819522

Positions:

• chr22-19779259-C-T

Variant summary

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

The ENST00000329705.11(TBX1):​c.1049C>T​(p.Thr350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,954 control chromosomes in the GnomAD database, including 32,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2689 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30108 hom.)
• Consequence: TBX1 ENST00000329705.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.779

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=0.0040336847).
• BP6: Variant 22-19779259-C-T is Benign according to our data. Variant chr22-19779259-C-T is described in ClinVar as [Benign]. Clinvar id is 403525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19779259-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_080646.2	c.1049C>T	p.Thr350Met	missense_variant	9/9		NP_542377.1
TBX1	NM_005992.1	c.1010-3654C>T		intron_variant			NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000329705.11	c.1049C>T	p.Thr350Met	missense_variant	9/9	1		ENSP00000331176	A2
TBX1	ENST00000359500.7	c.1010-3654C>T		intron_variant		1		ENSP00000352483	A2

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27860 AN: 152138 Hom.: 2682 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.212 AC: 53205 AN: 251322 Hom.: 6278 AF XY: 0.221 AC XY: 30004 AN XY: 135852

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.196 AC: 286251 AN: 1461700 Hom.: 30108 Cov.: 34 AF XY: 0.202 AC XY: 146791 AN XY: 727158

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.0981

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.183 AC: 27894 AN: 152254 Hom.: 2689 Cov.: 33 AF XY: 0.187 AC XY: 13955 AN XY: 74442

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.205

Alfa AF: 0.192 Hom.: 7727

Bravo AF: 0.182

TwinsUK AF: 0.191 AC: 709

ALSPAC AF: 0.185 AC: 713

ESP6500AA AF: 0.151 AC: 666

ESP6500EA AF: 0.183 AC: 1577

ExAC AF: 0.211 AC: 25627

Asia WGS AF: 0.233 AC: 809 AN: 3478

EpiCase AF: 0.197

EpiControl AF: 0.199

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00048	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.048	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.027
ClinPred		0.040	T
GERP RS		-3.4
Varity_R		0.016

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4819522; hg19: chr22-19766782; COSMIC: COSV61548397; COSMIC: COSV61548397;