17-61456594-C-T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.254

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=0.004457921).
• 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 GnomAd at 1305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.104C>T	p.Ala35Val	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2109G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.104C>T	p.Ala35Val	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.104C>T	p.Ala35Val	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.104C>T	p.Ala35Val	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-30C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00859 AC: 1305 AN: 151994 Hom.: 9 Cov.: 33

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.: 17 AF XY: 0.00882 AC XY: 603 AN XY: 68356

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.: 32 AF XY: 0.0115 AC XY: 7826 AN XY: 678202

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.: 9 Cov.: 33 AF XY: 0.00847 AC XY: 630 AN XY: 74354

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.: 5

Bravo AF: 0.00898

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0119 AC: 46

ExAC AF: 0.00556 AC: 225

Asia WGS AF: 0.000869 AC: 3 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TBX4: BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.71	D
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N;N;N;N
MutationTaster	Benign	0.73	N;N
PrimateAI	Pathogenic	0.83	D
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	T
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

Other links and lift over

dbSNP: rs148424252; hg19: chr17-59533955;