dbSNP rs104894648: TBX4:p.Gln62Lys (chr17-61456674-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001321120.2(TBX4):c.184C>A(p.Gln62Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,211,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense, splice_region

Scores

Splicing: ADA: 0.3466

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

0 publications found

Variant links:

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

TBX4 links:

LOC124904042 (HGNC:):

LOC124904042 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2760734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.184C>A	p.Gln62Lys	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000644296.1	NP_001308049.1	P57082-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1 link	c.184C>A	p.Gln62Lys	missense_variant, splice_region_variant	Exon 2 of 9		NM_001321120.2	ENSP00000495986.1		P57082-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.25e-7

AC:

AN:

1211890

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

591972

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24420

American (AMR)

AF:

0.00

AC:

AN:

17562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19570

East Asian (EAS)

AF:

0.00

AC:

AN:

26364

South Asian (SAS)

AF:

0.00

AC:

AN:

51146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3402

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

987716

Other (OTH)

AF:

0.00

AC:

AN:

48796

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;.;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.46

.;.;T;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.90

L;L;L;L

PhyloP100

1.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.63

N;.;N;.

REVEL

Benign

0.23

Sift

Uncertain

0.010

D;.;D;.

Sift4G

Benign

0.28

T;.;T;.

Polyphen

0.0010

.;.;B;.

Vest4

0.23

MutPred

0.50

Gain of ubiquitination at Q62 (P = 0.0077);Gain of ubiquitination at Q62 (P = 0.0077);Gain of ubiquitination at Q62 (P = 0.0077);Gain of ubiquitination at Q62 (P = 0.0077);

MVP

0.82

MPC

0.52

ClinPred

0.49

GERP RS

4.0

PromoterAI

0.045

Neutral

(source)

Varity_R

0.34

gMVP

0.55

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.35

dbscSNV1_RF

Benign

0.61

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over