chr12-114385563-G-A

Variant names:

• chr12-114385563-G-A
• rs1555225344
• NM_181486.4:c.668C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_181486.4(TBX5):​c.668C>T​(p.Thr223Met) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000616887: Published functional studies demonstrate that T223M interferes with the normal DNA-binding of the TBX5 protein (Stirnimann et al., 2010" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T223P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.49
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet
• heart conduction disease

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000616887: Published functional studies demonstrate that T223M interferes with the normal DNA-binding of the TBX5 protein (Stirnimann et al., 2010; Darwich et al., 2017; Markunas et al., 2021)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 12-114385563-G-A is Pathogenic according to our data. Variant chr12-114385563-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 449105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	NM_181486.4	MANE Select	c.668C>T	p.Thr223Met	missense	Exon 7 of 9	NP_852259.1	Q99593-1
	TBX5	NM_000192.3		c.668C>T	p.Thr223Met	missense	Exon 7 of 9	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.518C>T	p.Thr173Met	missense	Exon 6 of 8	NP_542448.1	Q99593-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.668C>T	p.Thr223Met	missense	Exon 7 of 9	ENSP00000384152.3	Q99593-1
	TBX5	ENST00000310346.8	TSL:1	c.668C>T	p.Thr223Met	missense	Exon 7 of 9	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.518C>T	p.Thr173Met	missense	Exon 6 of 8	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Holt-Oram syndrome (2)
1	-	-	Aortic valve disease 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.83		Gain of catalytic residue at Q218 (P = 0.0115)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.82
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs1555225344; hg19: chr12-114823368; COSMIC: COSV100092545;