rs754897911

chr17-61482983-TC-Tchr17-61482983-TC-TCC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001321120.2(TBX4):c.1115del(p.Pro372LeufsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBX4 NM_001321120.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61482983-TC-T is Pathogenic according to our data. Variant chr17-61482983-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548694.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr17-61482983-TC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.1115del	p.Pro372LeufsTer8	frameshift_variant	9/9	ENST00000644296.1
TBX4	NM_018488.3	c.1112del	p.Pro371LeufsTer8	frameshift_variant	8/8
TBX4	XM_011525490.3	c.1304del	p.Pro435LeufsTer8	frameshift_variant	9/9
TBX4	XM_011525491.3	c.1301del	p.Pro434LeufsTer8	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.1115del	p.Pro372LeufsTer8	frameshift_variant	9/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.1112del	p.Pro371LeufsTer8	frameshift_variant	8/8	1		P4
TBX4	ENST00000589449.5	n.874del		non_coding_transcript_exon_variant	7/8	1
TBX4	ENST00000642491.1	c.1115del	p.Pro372LeufsTer8	frameshift_variant	8/8			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250678 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461796 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 22, 2022

This premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 30029678, 30578397, 33066286). 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 sequence change creates a premature translational stop signal (p.Pro371Leufs*8) in the TBX4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 175 amino acid(s) of the TBX4 protein. ClinVar contains an entry for this variant (Variation ID: 548694). 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.Arg389Glnfs*30) 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. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only;research

Wendy Chung Laboratory, Columbia University Medical Center

Nov 01, 2019

- -

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

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;