12-114394847-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_181486.4(TBX5):c.557T>A(p.Val186Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V186G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a DNA_binding_region T-box (size 180) in uniprot entity TBX5_HUMAN there are 37 pathogenic changes around while only 4 benign (90%) in NM_181486.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.557T>A	p.Val186Glu	missense_variant	6/9	ENST00000405440.7
TBX5	NM_000192.3	c.557T>A	p.Val186Glu	missense_variant	6/9
TBX5	NM_080717.4	c.407T>A	p.Val136Glu	missense_variant	5/8
TBX5	XM_017019912.2	c.605T>A	p.Val202Glu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.557T>A	p.Val186Glu	missense_variant	6/9	1	NM_181486.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;.;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0, 0.96	.;D;D;D
Vest4		0.97
MutPred		0.79		.;Gain of disorder (P = 0.0023);Gain of disorder (P = 0.0023);Gain of disorder (P = 0.0023);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-114832652;