chr12-114401863-C-T

Position:

• chr12-114401863-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_181486.4(TBX5):​c.205G>A​(p.Glu69Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a DNA_binding_region T-box (size 180) in uniprot entity TBX5_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_181486.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.205G>A	p.Glu69Lys	missense_variant	3/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.205G>A	p.Glu69Lys	missense_variant	3/9		NP_000183.2
TBX5	NM_080717.4	c.55G>A	p.Glu19Lys	missense_variant	2/8		NP_542448.1
TBX5	XM_017019912.2	c.253G>A	p.Glu85Lys	missense_variant	3/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.205G>A	p.Glu69Lys	missense_variant	3/9	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;T;.
Eigen	Benign	-0.089
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.41	.;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.35	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.013, 0.027	.;B;B;B
Vest4		0.70
MutPred		0.50		.;Gain of catalytic residue at W64 (P = 0);Gain of catalytic residue at W64 (P = 0);Gain of catalytic residue at W64 (P = 0);
MVP		0.80
MPC		0.86
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894377; hg19: chr12-114839668; COSMIC: COSV59858590;