17-61456524-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001321120.2(TBX4):c.34G>A(p.Glu12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000914 in 1,565,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

Genes affected

TBX4 (HGNC:11603): (T-box transcription factor 4) 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 is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

LOC124904042 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12698871).
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.34G>A	p.Glu12Lys	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2179C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.34G>A	p.Glu12Lys	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.34G>A	p.Glu12Lys	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.34G>A	p.Glu12Lys	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-100G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 17 AN: 169496 Hom.: 0 AF XY: 0.0000987 AC XY: 9 AN XY: 91202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000899 AC: 127 AN: 1413162 Hom.: 0 Cov.: 32 AF XY: 0.0000888 AC XY: 62 AN XY: 698548

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.0000408

Gnomad4 NFE exome AF: 0.0000901

Gnomad4 OTH exome AF: 0.0000684

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000882 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 12 of the TBX4 protein (p.Glu12Lys). This variant is present in population databases (rs756802394, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TBX4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBX4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L;L;L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.65	N;.;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.047	D;.;D;.
Polyphen		0.013	.;.;B;.
Vest4		0.47
MutPred		0.39		Gain of ubiquitination at E12 (P = 0.0051);Gain of ubiquitination at E12 (P = 0.0051);Gain of ubiquitination at E12 (P = 0.0051);Gain of ubiquitination at E12 (P = 0.0051);
MVP		0.76
MPC		1.2
ClinPred		0.16	T
GERP RS		3.6
Varity_R		0.28
gMVP		0.49

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: rs756802394; hg19: chr17-59533885;