rs754897911

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001321120.2(TBX4):c.1115delC(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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts 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:

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ACMG classification

Classification made for transcript

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 0.321 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 [Likely_pathogenic]. Clinvar id is 548694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61482983-TC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.1115delC	p.Pro372LeufsTer8	frameshift_variant	Exon 9 of 9	ENST00000644296.1	NP_001308049.1	P57082-2
TBX4	NM_018488.3 link	c.1112delC	p.Pro371LeufsTer8	frameshift_variant	Exon 8 of 8		NP_060958.2	P57082-1
TBX4	XM_011525490.3 link	c.1304delC	p.Pro435LeufsTer8	frameshift_variant	Exon 9 of 9		XP_011523792.1
TBX4	XM_011525491.3 link	c.1301delC	p.Pro434LeufsTer8	frameshift_variant	Exon 9 of 9		XP_011523793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX4	ENST00000644296.1 link	c.1115delC	p.Pro372LeufsTer8	frameshift_variant	Exon 9 of 9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 link	c.1112delC	p.Pro371LeufsTer8	frameshift_variant	Exon 8 of 8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000589449.5 link	n.874delC		non_coding_transcript_exon_variant	Exon 7 of 8	1
TBX4	ENST00000642491.1 link	c.1115delC	p.Pro372LeufsTer8	frameshift_variant	Exon 8 of 8			ENSP00000495714.1	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. 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 premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 30029678, 30578397, 33066286). ClinVar contains an entry for this variant (Variation ID: 548694). 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

Nov 01, 2019

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only;research

- -

Pulmonary arterial hypertension associated with congenital heart disease

Uncertain:1

Jun 27, 2018

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: case-control

- -

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