rs28936696

Variant names:

• chr17-61483470-A-G
• rs28936696
• NM_001321120.2:c.1595A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-61483470-A-G
• chr17-61483470-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001321120.2(TBX4):​c.1595A>G​(p.Gln532Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.44
• Publications: 6 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, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• pulmonary arterial hypertension

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 17-61483470-A-G is Pathogenic according to our data. Variant chr17-61483470-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7857.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	NM_001321120.2	MANE Select	c.1595A>G	p.Gln532Arg	missense	Exon 9 of 9	NP_001308049.1	P57082-2
	TBX4	NM_018488.3		c.1592A>G	p.Gln531Arg	missense	Exon 8 of 8	NP_060958.2	P57082-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	ENST00000644296.1	MANE Select	c.1595A>G	p.Gln532Arg	missense	Exon 9 of 9	ENSP00000495986.1	P57082-2
	TBX4	ENST00000240335.1	TSL:1	c.1592A>G	p.Gln531Arg	missense	Exon 8 of 8	ENSP00000240335.1	P57082-1
	TBX4	ENST00000642491.1		c.1595A>G	p.Gln532Arg	missense	Exon 8 of 8	ENSP00000495714.1	P57082-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Coxopodopatellar syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.80	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.60	P
Vest4		0.80
MutPred		0.74		Gain of catalytic residue at Q531 (P = 0.0352)
MVP		0.84
MPC		0.69
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.70
Mutation Taster		=11/89	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: rs28936696; hg19: chr17-59560831;