rs104894384

Variant names:

• chr12-114401907-A-G
• rs104894384
• NM_181486.4:c.161T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_181486.4(TBX5):​c.161T>C​(p.Ile54Thr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.82
• Publications: 10 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 12-114401907-A-G is Pathogenic according to our data. Variant chr12-114401907-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7998.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.161T>C	p.Ile54Thr	missense_variant	Exon 3 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.161T>C	p.Ile54Thr	missense_variant	Exon 3 of 9		NP_000183.2
TBX5	NM_080717.4	c.11T>C	p.Ile4Thr	missense_variant	Exon 2 of 8		NP_542448.1
TBX5	XM_017019912.2	c.209T>C	p.Ile70Thr	missense_variant	Exon 3 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.161T>C	p.Ile54Thr	missense_variant	Exon 3 of 9	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.000548 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Holt-Oram syndrome Pathogenic:1

Jun 05, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;D;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.97	.;L;L;L
PhyloP100		8.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;T
Polyphen		0.096, 0.33	.;B;B;B
Vest4		0.88
MutPred		0.82		.;Gain of catalytic residue at F57 (P = 0.0157);Gain of catalytic residue at F57 (P = 0.0157);Gain of catalytic residue at F57 (P = 0.0157);
MVP		0.99
MPC		1.0
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.85
Mutation Taster		=5/95	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: rs104894384; hg19: chr12-114839712;