17-61482983-TC-TCC

Position:

• chr17-61482983-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001321120.2(TBX4):​c.1115dupC​(p.Pro373fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX4 NM_001321120.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 7.57

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.32 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61482983-T-TC is Pathogenic according to our data. Variant chr17-61482983-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.1115dupC	p.Pro373fs	frameshift_variant	9/9	ENST00000644296.1	NP_001308049.1
TBX4	NM_018488.3	c.1112dupC	p.Pro372fs	frameshift_variant	8/8		NP_060958.2
TBX4	XM_011525490.3	c.1304dupC	p.Pro436fs	frameshift_variant	9/9		XP_011523792.1
TBX4	XM_011525491.3	c.1301dupC	p.Pro435fs	frameshift_variant	9/9		XP_011523793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.1115dupC	p.Pro373fs	frameshift_variant	9/9		NM_001321120.2	ENSP00000495986.1
TBX4	ENST00000240335.1	c.1112dupC	p.Pro372fs	frameshift_variant	8/8	1		ENSP00000240335.1
TBX4	ENST00000589449.5	n.874dupC		non_coding_transcript_exon_variant	7/8	1
TBX4	ENST00000642491.1	c.1115dupC	p.Pro373fs	frameshift_variant	8/8			ENSP00000495714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461790 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Primary pulmonary hypoplasia;C1840061:Coxopodopatellar syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Stankiewicz Research Laboratory, Baylor College of Medicine

-

Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2023

ClinVar contains an entry for this variant (Variation ID: 812880). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TBX4 protein in which other variant(s) (p.Gln531Arg) have been determined to be pathogenic (PMID: 15106123). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with TBX4-related conditions (PMID: 15106123, 29650961, 30578397, 32860008). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro372Serfs*14) in the TBX4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 174 amino acid(s) of the TBX4 protein. -

Coxopodopatellar syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

- -

Coxopodopatellar syndrome;C4552070:Pulmonary hypertension, primary, 1 Other:1

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

-

- -

Pulmonary hypertension, primary, 1 Other:1

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs754897911; hg19: chr17-59560344;