rs41298838

Variant names:

• chr22-19765921-G-A
• rs41298838
• NM_001379200.1:c.955G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19765921-G-A
• chr22-19765921-G-C
• chr22-19765921-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379200.1(TBX1):​c.955G>A​(p.Gly319Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,535,450 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G319A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (66 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 5.03
• Publications: 29 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, STRONG Submitted by: PanelApp Australia, 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 (MetaRNN=0.0026478171).
• BP6: Variant 22-19765921-G-A is Benign according to our data. Variant chr22-19765921-G-A is described in ClinVar as Benign. ClinVar VariationId is 7564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00199 (303/152016) while in subpopulation EAS AF = 0.0521 (267/5128). AF 95% confidence interval is 0.0469. There are 5 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 303 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379200.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_001379200.1	MANE Select	c.955G>A	p.Gly319Ser	missense	Exon 6 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.928G>A	p.Gly310Ser	missense	Exon 8 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.928G>A	p.Gly310Ser	missense	Exon 8 of 9	NP_542377.1	O43435-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.955G>A	p.Gly319Ser	missense	Exon 6 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.928G>A	p.Gly310Ser	missense	Exon 8 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.928G>A	p.Gly310Ser	missense	Exon 8 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 151906 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00521 AC: 676 AN: 129680 AF XY: 0.00466

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000219

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00137 AC: 1899 AN: 1383434 Hom.: 66 Cov.: 31 AF XY: 0.00134 AC XY: 916 AN XY: 682132

African (AFR) AF: 0.0000657 AC: 2 AN: 30444

American (AMR) AF: 0.000174 AC: 6 AN: 34576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24642

East Asian (EAS) AF: 0.0474 AC: 1613 AN: 34058

South Asian (SAS) AF: 0.000333 AC: 26 AN: 78166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5114

European-Non Finnish (NFE) AF: 0.0000251 AC: 27 AN: 1073748

Other (OTH) AF: 0.00393 AC: 225 AN: 57236

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152016 Hom.: 5 Cov.: 33 AF XY: 0.00233 AC XY: 173 AN XY: 74300

African (AFR) AF: 0.000217 AC: 9 AN: 41502

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0521 AC: 267 AN: 5128

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67918

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000303 Hom.: 1

Bravo AF: 0.00227

ExAC AF: 0.00292 AC: 172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	2	DiGeorge syndrome (3)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.35
Sift	Benign	0.15	T
Sift4G	Benign	0.32	T
Polyphen		0.83	P
Vest4		0.67
MVP		0.60
MPC		1.5
ClinPred		0.076	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.49
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41298838; hg19: chr22-19753444;