rs758596

Positions:

chr17-61467502-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001321120.2(TBX4):c.402-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,882 control chromosomes in the GnomAD database, including 64,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7882 hom., cov: 33)

Exomes 𝑓: 0.27 ( 56250 hom. )

Consequence

TBX4
NM_001321120.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003001

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 17-61467502-G-A is Benign according to our data. Variant chr17-61467502-G-A is described in ClinVar as [Benign]. Clinvar id is 261034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61467502-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2 linkuse as main transcript	c.402-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644296.1	NP_001308049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.402-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001321120.2	ENSP00000495986	A1	P57082-2

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47236

AN:

152034

Hom.:

7879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.304

GnomAD3 exomes

AF:

0.275

AC:

68996

AN:

251116

Hom.:

9993

AF XY:

0.275

AC XY:

37338

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.431

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.367

Gnomad SAS exome

AF:

0.301

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.275

AC:

401389

AN:

1461728

Hom.:

56250

Cov.:

AF XY:

0.274

AC XY:

199410

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.435

Gnomad4 AMR exome

AF:

0.189

Gnomad4 ASJ exome

AF:

0.282

Gnomad4 EAS exome

AF:

0.356

Gnomad4 SAS exome

AF:

0.296

Gnomad4 FIN exome

AF:

0.224

Gnomad4 NFE exome

AF:

0.270

Gnomad4 OTH exome

AF:

0.286

GnomAD4 genome

AF:

0.311

AC:

47269

AN:

152154

Hom.:

7882

Cov.:

AF XY:

0.305

AC XY:

22715

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.427

Gnomad4 AMR

AF:

0.218

Gnomad4 ASJ

AF:

0.279

Gnomad4 EAS

AF:

0.359

Gnomad4 SAS

AF:

0.310

Gnomad4 FIN

AF:

0.212

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.301

Alfa

AF:

0.281

Hom.:

8278

Bravo

AF:

0.315

Asia WGS

AF:

0.345

AC:

1200

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.274

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Coxopodopatellar syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive amelia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.0

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

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