rs758596

Variant names:

• chr17-61467502-G-A
• rs758596
• NM_001321120.2:c.402-8G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001321120.2(TBX4):​c.402-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,882 control chromosomes in the GnomAD database, including 64,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7882 hom., cov: 33)
  • Exomes 𝑓: 0.27 (56250 hom.)
• Consequence: TBX4 NM_001321120.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003001
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.58
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-61467502-G-A is Benign according to our data. Variant chr17-61467502-G-A is described in ClinVar as Benign. ClinVar VariationId is 261034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 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.402-8G>A		splice_region intron	N/A	NP_001308049.1
	TBX4	NM_018488.3		c.402-8G>A		splice_region intron	N/A	NP_060958.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX4	ENST00000644296.1	MANE Select	c.402-8G>A		splice_region intron	N/A	ENSP00000495986.1
	TBX4	ENST00000240335.1	TSL:1	c.402-8G>A		splice_region intron	N/A	ENSP00000240335.1
	TBX4	ENST00000642491.1		c.402-8G>A		splice_region intron	N/A	ENSP00000495714.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47236 AN: 152034 Hom.: 7879 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.275 AC: 68996 AN: 251116 AF XY: 0.275

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.275 AC: 401389 AN: 1461728 Hom.: 56250 Cov.: 39 AF XY: 0.274 AC XY: 199410 AN XY: 727162

African (AFR) AF: 0.435 AC: 14569 AN: 33478

American (AMR) AF: 0.189 AC: 8443 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 7357 AN: 26134

East Asian (EAS) AF: 0.356 AC: 14143 AN: 39698

South Asian (SAS) AF: 0.296 AC: 25510 AN: 86256

European-Finnish (FIN) AF: 0.224 AC: 11938 AN: 53402

Middle Eastern (MID) AF: 0.249 AC: 1438 AN: 5766

European-Non Finnish (NFE) AF: 0.270 AC: 300738 AN: 1111886

Other (OTH) AF: 0.286 AC: 17253 AN: 60392

GnomAD4 genome AF: 0.311 AC: 47269 AN: 152154 Hom.: 7882 Cov.: 33 AF XY: 0.305 AC XY: 22715 AN XY: 74392

African (AFR) AF: 0.427 AC: 17727 AN: 41472

American (AMR) AF: 0.218 AC: 3327 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3468

East Asian (EAS) AF: 0.359 AC: 1860 AN: 5174

South Asian (SAS) AF: 0.310 AC: 1498 AN: 4828

European-Finnish (FIN) AF: 0.212 AC: 2249 AN: 10602

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18698 AN: 67994

Other (OTH) AF: 0.301 AC: 636 AN: 2114

Alfa AF: 0.284 Hom.: 10431

Bravo AF: 0.315

Asia WGS AF: 0.345 AC: 1200 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.274

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Coxopodopatellar syndrome (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive amelia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.0
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: rs758596; hg19: chr17-59544863; COSMIC: COSV53605952; COSMIC: COSV53605952;