17-61456594-C-T

Position:

chr17-61456594-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001321120.2(TBX4):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,527,750 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 9 hom., cov: 33)

Exomes 𝑓: 0.012 ( 133 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.254

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004457921).

BP6

Variant 17-61456594-C-T is Benign according to our data. Variant chr17-61456594-C-T is described in ClinVar as [Benign]. Clinvar id is 324243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61456594-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00858 (1305/152102) while in subpopulation AMR AF= 0.0144 (220/15288). AF 95% confidence interval is 0.0128. There are 9 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	2/9	ENST00000644296.1	NP_001308049.1	P57082-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	2/9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 linkuse as main transcript	c.-125-30C>T		intron_variant		3		ENSP00000467588.1	K7EPY2

Frequencies

GnomAD3 genomes

AF:

0.00859

AC:

1305

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000569

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.00941

AC:

1178

AN:

125246

Hom.:

AF XY:

0.00882

AC XY:

603

AN XY:

68356

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.000758

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0119

AC:

16388

AN:

1375648

Hom.:

133

Cov.:

AF XY:

0.0115

AC XY:

7826

AN XY:

678202

show subpopulations

Gnomad4 AFR exome

AF:

0.00226

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0232

Gnomad4 EAS exome

AF:

0.0000586

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.000826

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.00858

AC:

1305

AN:

152102

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

630

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000569

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0121

Hom.:

Bravo

AF:

0.00898

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0119

AC:

ExAC

AF:

0.00556

AC:

225

Asia WGS

AF:

0.000869

AC:

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TBX4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -

Coxopodopatellar syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

.;.;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.42

.;.;T;T

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.34

N;N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.97

N;.;N;.

REVEL

Benign

0.19

Sift

Benign

0.074

T;.;T;.

Sift4G

Benign

0.26

T;.;T;.

Polyphen

0.0060

.;.;B;.

Vest4

0.068

MVP

0.71

MPC

0.40

ClinPred

0.0029

GERP RS

2.3

Varity_R

0.072

gMVP

0.35

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

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