17-61456581-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321120.2(TBX4):c.91G>A(p.Glu31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19168305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.91G>A	p.Glu31Lys	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2122C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.91G>A	p.Glu31Lys	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.91G>A	p.Glu31Lys	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.91G>A	p.Glu31Lys	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-43G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000151 AC: 2 AN: 132738 Hom.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 72058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383354 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 682000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.0000408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000315 Hom.: 0

Bravo AF: 0.00000378

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

Sep 21, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 31 of the TBX4 protein (p.Glu31Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. 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	Benign	0.18
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.060	N;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.079	T;.;T;.
Sift4G	Benign	0.79	T;.;T;.
Polyphen		0.015	.;.;B;.
Vest4		0.24
MutPred		0.29		Gain of ubiquitination at E31 (P = 0.0037);Gain of ubiquitination at E31 (P = 0.0037);Gain of ubiquitination at E31 (P = 0.0037);Gain of ubiquitination at E31 (P = 0.0037);
MVP		0.78
MPC		0.46
ClinPred		0.11	T
GERP RS		3.4
Varity_R		0.20
gMVP		0.31

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: rs1354010581; hg19: chr17-59533942;