12-114355544-G-T

Position:

• chr12-114355544-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181486.4(TBX5):​c.1545C>A​(p.Ser515Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48

Genes affected

TBX5 (HGNC:11604): (T-box transcription factor 5) 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 closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15254611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.1545C>A	p.Ser515Arg	missense_variant	9/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.1545C>A	p.Ser515Arg	missense_variant	9/9		NP_000183.2
TBX5	NM_080717.4	c.1395C>A	p.Ser465Arg	missense_variant	8/8		NP_542448.1
TBX5	XM_017019912.2	c.1593C>A	p.Ser531Arg	missense_variant	9/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.1545C>A	p.Ser515Arg	missense_variant	9/9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.1545C>A	p.Ser515Arg	missense_variant	9/9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.1395C>A	p.Ser465Arg	missense_variant	8/8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251264 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBX5 protein function. This variant has not been reported in the literature in individuals affected with TBX5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 515 of the TBX5 protein (p.Ser515Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.072
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.34	.;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.50	.;P;P
Vest4		0.44
MutPred		0.19		.;Gain of catalytic residue at E513 (P = 0.0061);Gain of catalytic residue at E513 (P = 0.0061);
MVP		0.40
MPC		0.18
ClinPred		0.64	D
GERP RS		-8.1
Varity_R		0.24
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs186780790; hg19: chr12-114793349;