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. 15/25 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

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 links:

LOC124904042 (HGNC:):

LOC124904042 links:

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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

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

24420

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

17562

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19570

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

26364

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

51146

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

32914

Gnomad4 NFE exome

AF:

0.00000101

AC:

AN:

987716

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

48796

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

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

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

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

Varity_R

0.34

gMVP

0.55

Mutation Taster

=63/37

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over