rs2270150

chr17-61483324-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001321120.2(TBX4):c.1449C>T(p.Val483=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,610,470 control chromosomes in the GnomAD database, including 14,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1368 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12709 hom.)
• Consequence: TBX4 NM_001321120.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00300

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-61483324-C-T is Benign according to our data. Variant chr17-61483324-C-T is described in ClinVar as [Benign]. Clinvar id is 261033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61483324-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.1449C>T	p.Val483=	synonymous_variant	9/9	ENST00000644296.1
TBX4	NM_018488.3	c.1446C>T	p.Val482=	synonymous_variant	8/8
TBX4	XM_011525490.3	c.1638C>T	p.Val546=	synonymous_variant	9/9
TBX4	XM_011525491.3	c.1635C>T	p.Val545=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.1449C>T	p.Val483=	synonymous_variant	9/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.1446C>T	p.Val482=	synonymous_variant	8/8	1		P4
TBX4	ENST00000589449.5	n.1115C>T		non_coding_transcript_exon_variant	8/8	1
TBX4	ENST00000642491.1	c.1449C>T	p.Val483=	synonymous_variant	8/8			A1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19428 AN: 152094 Hom.: 1365 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0922

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.113 AC: 28301 AN: 250294 Hom.: 1774 AF XY: 0.115 AC XY: 15527 AN XY: 135250

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0648

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0196

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.130 AC: 189627 AN: 1458258 Hom.: 12709 Cov.: 37 AF XY: 0.130 AC XY: 94008 AN XY: 724694

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0321

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.128 AC: 19437 AN: 152212 Hom.: 1368 Cov.: 32 AF XY: 0.126 AC XY: 9378 AN XY: 74410

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0921

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.117

Alfa AF: 0.135 Hom.: 2414

Bravo AF: 0.123

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.139

EpiControl AF: 0.141

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: MAF -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -

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
BayesDel_noAF	Benign	-0.44
Cadd	Benign	6.2
Dann	Benign	0.74

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: rs2270150; hg19: chr17-59560685; COSMIC: COSV53607158; COSMIC: COSV53607158;