rs28936696

Positions:

• chr17-61483470-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 7857.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.1595A>G	p.Gln532Arg	missense_variant	9/9	ENST00000644296.1	NP_001308049.1
TBX4	NM_018488.3	c.1592A>G	p.Gln531Arg	missense_variant	8/8		NP_060958.2
TBX4	XM_011525490.3	c.1784A>G	p.Gln595Arg	missense_variant	9/9		XP_011523792.1
TBX4	XM_011525491.3	c.1781A>G	p.Gln594Arg	missense_variant	9/9		XP_011523793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.1595A>G	p.Gln532Arg	missense_variant	9/9		NM_001321120.2	ENSP00000495986.1
TBX4	ENST00000240335.1	c.1592A>G	p.Gln531Arg	missense_variant	8/8	1		ENSP00000240335.1
TBX4	ENST00000642491.1	c.1595A>G	p.Gln532Arg	missense_variant	8/8			ENSP00000495714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Coxopodopatellar syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -
not provided, no classification provided	literature only	Wendy Chung Laboratory, Columbia University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.1	.;.;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.80	N;.;N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs28936696; hg19: chr17-59560831;