rs3744448

Variant names:

• chr17-61456507-G-C
• rs3744448
• NM_001321120.2:c.17G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-61456507-G-C
• chr17-61456507-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001321120.2(TBX4):​c.17G>C​(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,568,454 control chromosomes in the GnomAD database, including 20,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2019 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18527 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.06
• Publications: 37 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• pulmonary arterial hypertension

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

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P
• 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=0.0018821359).
• BP6: Variant 17-61456507-G-C is Benign according to our data. Variant chr17-61456507-G-C is described in ClinVar as Benign. ClinVar VariationId is 324241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 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.17G>C	p.Gly6Ala	missense	Exon 2 of 9	NP_001308049.1	P57082-2
	TBX4	NM_018488.3		c.17G>C	p.Gly6Ala	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.17G>C	p.Gly6Ala	missense	Exon 2 of 9	ENSP00000495986.1	P57082-2
	TBX4	ENST00000240335.1	TSL:1	c.17G>C	p.Gly6Ala	missense	Exon 1 of 8	ENSP00000240335.1	P57082-1
	TBX4	ENST00000642491.1		c.17G>C	p.Gly6Ala	missense	Exon 1 of 8	ENSP00000495714.1	P57082-2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23087 AN: 152020 Hom.: 2011 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.169 AC: 29958 AN: 177474 AF XY: 0.167

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.294

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.156 AC: 220921 AN: 1416316 Hom.: 18527 Cov.: 32 AF XY: 0.156 AC XY: 109566 AN XY: 700350

African (AFR) AF: 0.106 AC: 3434 AN: 32544

American (AMR) AF: 0.182 AC: 6935 AN: 38116

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3372 AN: 25248

East Asian (EAS) AF: 0.347 AC: 12898 AN: 37200

South Asian (SAS) AF: 0.164 AC: 13182 AN: 80314

European-Finnish (FIN) AF: 0.251 AC: 12375 AN: 49230

Middle Eastern (MID) AF: 0.173 AC: 979 AN: 5652

European-Non Finnish (NFE) AF: 0.145 AC: 158308 AN: 1089392

Other (OTH) AF: 0.161 AC: 9438 AN: 58620

GnomAD4 genome AF: 0.152 AC: 23114 AN: 152138 Hom.: 2019 Cov.: 33 AF XY: 0.158 AC XY: 11725 AN XY: 74376

African (AFR) AF: 0.108 AC: 4500 AN: 41564

American (AMR) AF: 0.163 AC: 2492 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3472

East Asian (EAS) AF: 0.316 AC: 1615 AN: 5114

South Asian (SAS) AF: 0.162 AC: 779 AN: 4822

European-Finnish (FIN) AF: 0.258 AC: 2741 AN: 10606

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10071 AN: 67952

Other (OTH) AF: 0.155 AC: 326 AN: 2110

Alfa AF: 0.154 Hom.: 1509

Bravo AF: 0.144

TwinsUK AF: 0.151 AC: 561

ALSPAC AF: 0.154 AC: 592

ESP6500AA AF: 0.105 AC: 456

ESP6500EA AF: 0.125 AC: 1074

ExAC AF: 0.114 AC: 13024

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.29
Sift	Benign	0.51	T
Sift4G	Benign	1.0	T
Polyphen		0.35	B
Vest4		0.084
MPC		0.48
ClinPred		0.018	T
GERP RS		4.3
PromoterAI		0.015	Neutral
Varity_R		0.14
gMVP		0.25
Mutation Taster		=91/9	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: rs3744448; hg19: chr17-59533868; COSMIC: COSV53605474; COSMIC: COSV53605474;