17-61456627-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001321120.2(TBX4):c.143dup(p.Pro50ThrfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,228,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TBX4 NM_001321120.2 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.368

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.143dup	p.Pro50ThrfsTer24	frameshift_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2075_2076insG		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.143dup	p.Pro50ThrfsTer24	frameshift_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.143dup	p.Pro50ThrfsTer24	frameshift_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.143dup	p.Pro50ThrfsTer24	frameshift_variant	1/8			A1
TBX4	ENST00000589003.5	c.-116dup		5_prime_UTR_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1228978 Hom.: 0 Cov.: 31 AF XY: 0.00000167 AC XY: 1 AN XY: 600252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000677

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: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-59533988;