17-61479927-G-A

Position:

• chr17-61479927-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001321120.2(TBX4):​c.749G>A​(p.Arg250Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.84

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]

TBX4 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a DNA_binding_region T-box (size 180) in uniprot entity TBX4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001321120.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-61479926-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 17-61479927-G-A is Pathogenic according to our data. Variant chr17-61479927-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548696.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.749G>A	p.Arg250Gln	missense_variant	7/9	ENST00000644296.1	NP_001308049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.749G>A	p.Arg250Gln	missense_variant	7/9		NM_001321120.2	ENSP00000495986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 250 of the TBX4 protein (p.Arg250Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital heart disease (PMID: 30029678). ClinVar contains an entry for this variant (Variation ID: 548696). 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 expected to disrupt TBX4 protein function. This variant disrupts the p.Arg250 amino acid residue in TBX4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23592887, 29120062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Wendy Chung Laboratory, Columbia University Medical Center

Jun 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;.;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.96
MutPred		0.93		Gain of ubiquitination at K247 (P = 0.0396);Gain of ubiquitination at K247 (P = 0.0396);Gain of ubiquitination at K247 (P = 0.0396);Gain of ubiquitination at K247 (P = 0.0396);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.78

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: rs1555883469; hg19: chr17-59557288;