17-61456600-C-T

Position:

• chr17-61456600-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321120.2(TBX4):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000296 in 1,351,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.46

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16744682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.110C>T	p.Pro37Leu	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2103G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.110C>T	p.Pro37Leu	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.110C>T	p.Pro37Leu	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.110C>T	p.Pro37Leu	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-24C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000945 AC: 1 AN: 105820 Hom.: 0 AF XY: 0.0000172 AC XY: 1 AN XY: 58096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000140

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000296 AC: 4 AN: 1351466 Hom.: 0 Cov.: 31 AF XY: 0.00000300 AC XY: 2 AN XY: 665898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000909

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.110C>T (p.P37L) alteration is located in exon 1 (coding exon 1) of the TBX4 gene. This alteration results from a C to T substitution at nucleotide position 110, causing the proline (P) at amino acid position 37 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Coxopodopatellar syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.83
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.37	N
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.34	N;N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;.;N;.
REVEL	Benign	0.20
Sift	Benign	0.18	T;.;T;.
Sift4G	Benign	0.10	T;.;T;.
Polyphen		0.015	.;.;B;.
Vest4		0.20
MutPred		0.25		Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);
MVP		0.67
MPC		0.41
ClinPred		0.085	T
GERP RS		3.3
Varity_R		0.17
gMVP		0.26

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: rs886053187; hg19: chr17-59533961;