17-61456493-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001321120.2(TBX4):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000706 in 1,417,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TBX4 NM_001321120.2 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.40

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61456493-G-A is Pathogenic according to our data. Variant chr17-61456493-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.3G>A	p.Met1?	start_lost	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2210C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.3G>A	p.Met1?	start_lost	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.3G>A	p.Met1?	start_lost	1/8	1		P4
TBX4	ENST00000642491.1	c.3G>A	p.Met1?	start_lost	1/8			A1
TBX4	ENST00000589003.5	c.-125-131G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417044 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 700756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Coxopodopatellar syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.61	N;.;N;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		0.27	.;.;B;.
Vest4		0.89
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.1388);Gain of catalytic residue at M1 (P = 0.1388);Gain of catalytic residue at M1 (P = 0.1388);Gain of catalytic residue at M1 (P = 0.1388);
MVP		0.84
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-59533854;