rs148424252

Variant names:

• chr17-61456594-C-T
• rs148424252
• NM_001321120.2:c.104C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0086 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (133 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.254
• Publications: 9 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 -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/Likely_benign. ClinVar VariationId is 324243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.104C>T	p.Ala35Val	missense	Exon 2 of 9	NP_001308049.1	P57082-2
	TBX4	NM_018488.3		c.104C>T	p.Ala35Val	missense	Exon 1 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.104C>T	p.Ala35Val	missense	Exon 2 of 9	ENSP00000495986.1	P57082-2
	TBX4	ENST00000240335.1	TSL:1	c.104C>T	p.Ala35Val	missense	Exon 1 of 8	ENSP00000240335.1	P57082-1
	TBX4	ENST00000642491.1		c.104C>T	p.Ala35Val	missense	Exon 1 of 8	ENSP00000495714.1	P57082-2

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

GnomAD2 exomes AF: 0.00941 AC: 1178 AN: 125246 AF XY: 0.00882

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 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

African (AFR) AF: 0.00226 AC: 67 AN: 29680

American (AMR) AF: 0.0112 AC: 383 AN: 34160

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 558 AN: 24026

East Asian (EAS) AF: 0.0000586 AC: 2 AN: 34114

South Asian (SAS) AF: 0.00195 AC: 150 AN: 77024

European-Finnish (FIN) AF: 0.000826 AC: 39 AN: 47200

Middle Eastern (MID) AF: 0.0108 AC: 45 AN: 4150

European-Non Finnish (NFE) AF: 0.0135 AC: 14389 AN: 1068570

Other (OTH) AF: 0.0133 AC: 755 AN: 56724

GnomAD4 genome AF: 0.00858 AC: 1305 AN: 152102 Hom.: 9 Cov.: 33 AF XY: 0.00847 AC XY: 630 AN XY: 74354

African (AFR) AF: 0.00238 AC: 99 AN: 41552

American (AMR) AF: 0.0144 AC: 220 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.000569 AC: 6 AN: 10552

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0128 AC: 873 AN: 67956

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Coxopodopatellar syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.25
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.19
Sift	Benign	0.074	T
Sift4G	Benign	0.26	T
Polyphen		0.0060	B
Vest4		0.068
MVP		0.71
MPC		0.40
ClinPred		0.0029	T
GERP RS		2.3
PromoterAI		-0.043	Neutral
Varity_R		0.072
gMVP		0.35
Mutation Taster		=100/0	polymorphism

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: rs148424252; hg19: chr17-59533955;