rs3744447

Variant names:

• chr17-61457626-T-G
• rs3744447
• NM_001321120.2:c.276T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-61457626-T-G
• chr17-61457626-T-A
• chr17-61457626-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001321120.2(TBX4):​c.276T>G​(p.Ala92Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,722 control chromosomes in the GnomAD database, including 26,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2379 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23737 hom.)
• Consequence: TBX4 NM_001321120.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.106
• Publications: 25 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, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• pulmonary arterial hypertension

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124904042 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-61457626-T-G is Benign according to our data. Variant chr17-61457626-T-G is described in ClinVar as Benign. ClinVar VariationId is 324249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.106 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321120.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	NM_001321120.2	MANE Select	c.276T>G	p.Ala92Ala	synonymous	Exon 3 of 9	NP_001308049.1	P57082-2
	TBX4	NM_018488.3		c.276T>G	p.Ala92Ala	synonymous	Exon 2 of 8	NP_060958.2	P57082-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	ENST00000644296.1	MANE Select	c.276T>G	p.Ala92Ala	synonymous	Exon 3 of 9	ENSP00000495986.1	P57082-2
	TBX4	ENST00000240335.1	TSL:1	c.276T>G	p.Ala92Ala	synonymous	Exon 2 of 8	ENSP00000240335.1	P57082-1
	TBX4	ENST00000642491.1		c.276T>G	p.Ala92Ala	synonymous	Exon 2 of 8	ENSP00000495714.1	P57082-2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25245 AN: 151516 Hom.: 2372 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.192 AC: 48109 AN: 251124 AF XY: 0.191

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.174 AC: 253722 AN: 1461088 Hom.: 23737 Cov.: 32 AF XY: 0.175 AC XY: 126997 AN XY: 726826

African (AFR) AF: 0.114 AC: 3799 AN: 33460

American (AMR) AF: 0.199 AC: 8882 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4690 AN: 26122

East Asian (EAS) AF: 0.378 AC: 15009 AN: 39688

South Asian (SAS) AF: 0.201 AC: 17295 AN: 86234

European-Finnish (FIN) AF: 0.277 AC: 14769 AN: 53310

Middle Eastern (MID) AF: 0.200 AC: 1153 AN: 5764

European-Non Finnish (NFE) AF: 0.159 AC: 177179 AN: 1111430

Other (OTH) AF: 0.181 AC: 10946 AN: 60370

GnomAD4 genome AF: 0.167 AC: 25275 AN: 151634 Hom.: 2379 Cov.: 32 AF XY: 0.173 AC XY: 12840 AN XY: 74090

African (AFR) AF: 0.116 AC: 4807 AN: 41328

American (AMR) AF: 0.173 AC: 2646 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3468

East Asian (EAS) AF: 0.344 AC: 1749 AN: 5084

South Asian (SAS) AF: 0.203 AC: 967 AN: 4764

European-Finnish (FIN) AF: 0.286 AC: 3012 AN: 10534

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10967 AN: 67898

Other (OTH) AF: 0.164 AC: 345 AN: 2102

Alfa AF: 0.161 Hom.: 2152

Bravo AF: 0.157

Asia WGS AF: 0.258 AC: 898 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Coxopodopatellar syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		-0.11
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744447; hg19: chr17-59534987; COSMIC: COSV53605630; COSMIC: COSV53605630;