rs1555882009

Variant names:

• chr17-61465830-C-G
• rs1555882009
• NM_001321120.2:c.293C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-61465830-C-G
• chr17-61465830-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001321120.2(TBX4):​c.293C>G​(p.Pro98Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P98A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001321120.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-61465829-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1185696.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-61465830-C-G is Pathogenic according to our data. Variant chr17-61465830-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548692.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.293C>G	p.Pro98Arg	missense_variant	Exon 4 of 9	ENST00000644296.1	NP_001308049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.293C>G	p.Pro98Arg	missense_variant	Exon 4 of 9		NM_001321120.2	ENSP00000495986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease Pathogenic:1

Jun 27, 2018

Wendy Chung Laboratory, Boston Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;.;.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;M;M;M
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.5	.;D;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;.
Polyphen		1.0	.;.;.;D;.
Vest4		0.98
MutPred		0.89		.;Gain of catalytic residue at P98 (P = 0.011);Gain of catalytic residue at P98 (P = 0.011);Gain of catalytic residue at P98 (P = 0.011);Gain of catalytic residue at P98 (P = 0.011);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555882009; hg19: chr17-59543191;