rs1555883338

Variant names:

• chr17-61478745-CCTT-C
• rs1555883338
• NM_001321120.2:c.670_672delTTC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_001321120.2(TBX4):​c.670_672delTTC​(p.Phe224del) variant causes a conservative inframe deletion 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)
• Consequence: TBX4 NM_001321120.2 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• coxopodopatellar syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive amelia

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001321120.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-61478745-CCTT-C is Pathogenic according to our data. Variant chr17-61478745-CCTT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548697.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321120.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	NM_001321120.2	MANE Select	c.670_672delTTC	p.Phe224del	conservative_inframe_deletion	Exon 6 of 9	NP_001308049.1
	TBX4	NM_018488.3		c.670_672delTTC	p.Phe224del	conservative_inframe_deletion	Exon 5 of 8	NP_060958.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	ENST00000644296.1	MANE Select	c.670_672delTTC	p.Phe224del	conservative_inframe_deletion	Exon 6 of 9	ENSP00000495986.1
	TBX4	ENST00000240335.1	TSL:1	c.670_672delTTC	p.Phe224del	conservative_inframe_deletion	Exon 5 of 8	ENSP00000240335.1
	TBX4	ENST00000589449.5	TSL:1	n.200_202delTTC		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Pulmonary arterial hypertension associated with congenital heart disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555883338; hg19: chr17-59556106;