17-61456506-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001321120.2(TBX4):c.16G>A(p.Gly6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,569,902 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.33

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=0.008429915).
• BP6: Variant 17-61456506-G-A is Benign according to our data. Variant chr17-61456506-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 324240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61456506-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (195/152298) while in subpopulation NFE AF= 0.00224 (152/68006). AF 95% confidence interval is 0.00195. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.16G>A	p.Gly6Ser	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2197C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.16G>A	p.Gly6Ser	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.16G>A	p.Gly6Ser	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.16G>A	p.Gly6Ser	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-118G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00109 AC: 195 AN: 179220 Hom.: 2 AF XY: 0.00106 AC XY: 102 AN XY: 96294

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000733

Gnomad ASJ exome AF: 0.000344

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000583

Gnomad FIN exome AF: 0.000733

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00185 AC: 2629 AN: 1417604 Hom.: 5 Cov.: 30 AF XY: 0.00171 AC XY: 1197 AN XY: 701024

Gnomad4 AFR exome AF: 0.000215

Gnomad4 AMR exome AF: 0.000731

Gnomad4 ASJ exome AF: 0.000554

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000498

Gnomad4 FIN exome AF: 0.000871

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74470

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00122

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000700 AC: 6

ExAC AF: 0.000732 AC: 85

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Apr 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TBX4: BS2 -

TBX4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.090
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.14	N;N;N;N
MutationTaster	Benign	0.79	N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.21	N;.;N;.
REVEL	Benign	0.16
Sift	Benign	0.20	T;.;T;.
Sift4G	Benign	0.52	T;.;T;.
Polyphen		0.034	.;.;B;.
Vest4		0.13
MVP		0.78
MPC		0.41
ClinPred		0.0094	T
GERP RS		4.3
Varity_R		0.085
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: rs117410176; hg19: chr17-59533867; COSMIC: COSV104591696; COSMIC: COSV104591696;