NM_001321120.2:c.-3-496C>G

Variant names:

• chr17-61455992-C-G
• rs11867179
• NM_001321120.2:c.-3-496C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321120.2(TBX4):​c.-3-496C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 152,124 control chromosomes in the GnomAD database, including 4,695 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4695 hom., cov: 33)
• Consequence: TBX4 NM_001321120.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 5 publications found

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]

TBX4 Gene-Disease associations (from GenCC):

• coxopodopatellar syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive amelia

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124904042 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2	c.-3-496C>G		intron_variant	Intron 1 of 8	ENST00000644296.1	NP_001308049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1	c.-3-496C>G		intron_variant	Intron 1 of 8		NM_001321120.2	ENSP00000495986.1
TBX4	ENST00000589003.5	c.-125-632C>G		intron_variant	Intron 1 of 5	3		ENSP00000467588.1

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36159 AN: 152004 Hom.: 4695 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.238 AC: 36159 AN: 152124 Hom.: 4695 Cov.: 33 AF XY: 0.236 AC XY: 17548 AN XY: 74370

African (AFR) AF: 0.171 AC: 7113 AN: 41506

American (AMR) AF: 0.202 AC: 3096 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3466

East Asian (EAS) AF: 0.322 AC: 1661 AN: 5152

South Asian (SAS) AF: 0.321 AC: 1552 AN: 4830

European-Finnish (FIN) AF: 0.217 AC: 2304 AN: 10604

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18674 AN: 67954

Other (OTH) AF: 0.243 AC: 512 AN: 2110

Alfa AF: 0.249 Hom.: 620

Bravo AF: 0.233

Asia WGS AF: 0.306 AC: 1063 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
DANN	Benign	0.69
PhyloP100		0.28
PromoterAI		-0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11867179; hg19: chr17-59533353;