rs3744448

chr17-61456507-G-Cchr17-61456507-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001321120.2(TBX4):c.17G>C(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,568,454 control chromosomes in the GnomAD database, including 20,546 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2019 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18527 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.06

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018821359).
• BP6: Variant 17-61456507-G-C is Benign according to our data. Variant chr17-61456507-G-C is described in ClinVar as [Benign]. Clinvar id is 324241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61456507-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.17G>C	p.Gly6Ala	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2196C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.17G>C	p.Gly6Ala	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.17G>C	p.Gly6Ala	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.17G>C	p.Gly6Ala	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-117G>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23087 AN: 152020 Hom.: 2011 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.169 AC: 29958 AN: 177474 Hom.: 2771 AF XY: 0.167 AC XY: 15880 AN XY: 95328

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.294

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.156 AC: 220921 AN: 1416316 Hom.: 18527 Cov.: 32 AF XY: 0.156 AC XY: 109566 AN XY: 700350

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.152 AC: 23114 AN: 152138 Hom.: 2019 Cov.: 33 AF XY: 0.158 AC XY: 11725 AN XY: 74376

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.155

Alfa AF: 0.154 Hom.: 1509

Bravo AF: 0.144

TwinsUK AF: 0.151 AC: 561

ALSPAC AF: 0.154 AC: 592

ESP6500AA AF: 0.105 AC: 456

ESP6500EA AF: 0.125 AC: 1074

ExAC AF: 0.114 AC: 13024

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30389748) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Coxopodopatellar syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Benign	0.91
Eigen	Benign	-0.11
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N;N
MutationTaster	Benign	0.70	P;P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.10	N;.;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.51	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.35	.;.;B;.
Vest4		0.084
MPC		0.48
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.25

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

Other links and lift over

dbSNP: rs3744448; hg19: chr17-59533868; COSMIC: COSV53605474; COSMIC: COSV53605474;