Variant 17-61456674-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5

The NM_001321120.2(TBX4):c.184C>T(p.Gln62Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBX4
NM_001321120.2 stop_gained, splice_region

Scores

Splicing: ADA: 0.9967

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.13

Variant links:

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 links:

LOC124904042 (HGNC:):

LOC124904042 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-61456674-C-T is Pathogenic according to our data. Variant chr17-61456674-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7856.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 linkuse as main transcript	c.184C>T	p.Gln62Ter	stop_gained, splice_region_variant	2/9	ENST00000644296.1	NP_001308049.1
LOC124904042	XR_007065872.1 linkuse as main transcript	n.2029G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.184C>T	p.Gln62Ter	stop_gained, splice_region_variant	2/9		NM_001321120.2	ENSP00000495986	A1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.184C>T	p.Gln62Ter	stop_gained, splice_region_variant	1/8	1		ENSP00000240335	P4	P57082-1
TBX4	ENST00000642491.1 linkuse as main transcript	c.184C>T	p.Gln62Ter	stop_gained, splice_region_variant	1/8			ENSP00000495714	A1	P57082-2
TBX4	ENST00000589003.5 linkuse as main transcript	c.-75C>T		splice_region_variant, 5_prime_UTR_variant	2/6	3		ENSP00000467588

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1211890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

591972

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Coxopodopatellar syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.85

MutationTaster

Benign

1.0

A;A

Vest4

0.82

GERP RS

4.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.85

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over