17-61456527-GCCTTCCGGGC-G

Variant names:

• chr17-61456527-GCCTTCCGGGC-G
• rs1603248167
• NM_001321120.2:c.40_49delTTCCGGGCCC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001321120.2(TBX4):​c.40_49delTTCCGGGCCC​(p.Phe14ArgfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX4 NM_001321120.2 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.55

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 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61456527-GCCTTCCGGGC-G is Pathogenic according to our data. Variant chr17-61456527-GCCTTCCGGGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812874.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.40_49delTTCCGGGCCC	p.Phe14ArgfsTer28	frameshift_variant	Exon 2 of 9	ENST00000644296.1	NP_001308049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.40_49delTTCCGGGCCC	p.Phe14ArgfsTer28	frameshift_variant	Exon 2 of 9		NM_001321120.2	ENSP00000495986.1
TBX4	ENST00000240335.1	c.40_49delTTCCGGGCCC	p.Phe14ArgfsTer28	frameshift_variant	Exon 1 of 8	1		ENSP00000240335.1
TBX4	ENST00000642491.1	c.40_49delTTCCGGGCCC	p.Phe14ArgfsTer28	frameshift_variant	Exon 1 of 8			ENSP00000495714.1
TBX4	ENST00000589003.5	c.-125-94_-125-85delTTCCGGGCCC		intron_variant	Intron 1 of 5	3		ENSP00000467588.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Pulmonary hypertension, primary, 1 Other:1

-

Wendy Chung Laboratory, Boston Children's Hospital

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1603248167; hg19: chr17-59533888;