rs754897911

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Fraction of 0.324 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-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: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}. Variant chr17-61482983-TC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBX4	NM_001321120.2 linkuse as main transcript	c.1115del	p.Pro372LeufsTer8	frameshift_variant	9/9	ENST00000644296.1	NP_001308049.1
TBX4	NM_018488.3 linkuse as main transcript	c.1112del	p.Pro371LeufsTer8	frameshift_variant	8/8		NP_060958.2
TBX4	XM_011525490.3 linkuse as main transcript	c.1304del	p.Pro435LeufsTer8	frameshift_variant	9/9		XP_011523792.1
TBX4	XM_011525491.3 linkuse as main transcript	c.1301del	p.Pro434LeufsTer8	frameshift_variant	9/9		XP_011523793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.1115del	p.Pro372LeufsTer8	frameshift_variant	9/9		NM_001321120.2	ENSP00000495986	A1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.1112del	p.Pro371LeufsTer8	frameshift_variant	8/8	1		ENSP00000240335	P4	P57082-1
TBX4	ENST00000589449.5 linkuse as main transcript	n.874del		non_coding_transcript_exon_variant	7/8	1
TBX4	ENST00000642491.1 linkuse as main transcript	c.1115del	p.Pro372LeufsTer8	frameshift_variant	8/8			ENSP00000495714	A1	P57082-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250678

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135532

show subpopulations

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:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over