Genetic Variant TBX5:p.Asp111His (chr12-114399544-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_181486.4(TBX5):c.331G>C(p.Asp111His) variant causes a missense change. 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. D111Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Publications

0 publications found

Variant links:

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

TBX5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_181486.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX5	NM_181486.4	MANE Select	c.331G>C	p.Asp111His	missense	Exon 4 of 9	NP_852259.1	Q99593-1
TBX5	NM_000192.3		c.331G>C	p.Asp111His	missense	Exon 4 of 9	NP_000183.2	Q99593-1
TBX5	NM_080717.4		c.181G>C	p.Asp61His	missense	Exon 3 of 8	NP_542448.1	Q99593-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX5	ENST00000405440.7	TSL:1 MANE Select	c.331G>C	p.Asp111His	missense	Exon 4 of 9	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8	TSL:1	c.331G>C	p.Asp111His	missense	Exon 4 of 9	ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9	TSL:1	c.181G>C	p.Asp61His	missense	Exon 3 of 8	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.9

PhyloP100

6.2

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.87

MutPred

0.61

Gain of catalytic residue at D110 (P = 0.001)

MVP

0.94

MPC

2.0

ClinPred

1.0

GERP RS

4.7

Varity_R

0.88

gMVP

0.73

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over