chr12-114355544-G-T

Variant names:

• chr12-114355544-G-T
• rs186780790
• NM_181486.4:c.1545C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S515N) has been classified 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
• Publications: 3 publications found

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]

TBX5 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	NM_181486.4	MANE Select	c.1545C>A	p.Ser515Arg	missense	Exon 9 of 9	NP_852259.1
	TBX5	NM_000192.3		c.1545C>A	p.Ser515Arg	missense	Exon 9 of 9	NP_000183.2
	TBX5	NM_080717.4		c.1395C>A	p.Ser465Arg	missense	Exon 8 of 8	NP_542448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.1545C>A	p.Ser515Arg	missense	Exon 9 of 9	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.1545C>A	p.Ser515Arg	missense	Exon 9 of 9	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.1395C>A	p.Ser465Arg	missense	Exon 8 of 8	ENSP00000337723.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251264 AF XY: 0.00000736

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 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

Sep 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with TBX5-related conditions. 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). This variant is not present in population databases (gnomAD no frequency). 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. 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.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		0.50	P
Vest4		0.44
MutPred		0.19		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
Mutation Taster		=73/27	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: rs186780790; hg19: chr12-114793349;