rs1057519050

Positions:

• chr12-114398679-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_181486.4(TBX5):​c.404T>G​(p.Leu135Arg) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.49

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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_181486.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 12-114398679-A-C is Pathogenic according to our data. Variant chr12-114398679-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375289.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.404T>G	p.Leu135Arg	missense_variant	5/9	ENST00000405440.7
TBX5	NM_000192.3	c.404T>G	p.Leu135Arg	missense_variant	5/9
TBX5	NM_080717.4	c.254T>G	p.Leu85Arg	missense_variant	4/8
TBX5	XM_017019912.2	c.452T>G	p.Leu151Arg	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.404T>G	p.Leu135Arg	missense_variant	5/9	1	NM_181486.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial atrioventricular septal defect Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Human Genetics and Genome Research Institute, National Research Centre

Jun 01, 2016

Genomic DNA was extracted and followed by the Sanger sequencing and bioinformatics analysis. Analysis included computational predictions by MutationTaster2, Swiss-PdbViewer, The Ensembl Variant Effect Predictor, Protein Homology/analogY Recognition Engine V 2.0 (Phyre 2), DNA Baser v4.7.0.0, SNPnexus, Lasergene 6.0, NNSPLICE 0.9, and RegRNA 1.0. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0, 0.73	.;D;D;P
Vest4		0.93
MutPred		0.66		.;Gain of disorder (P = 0.0123);Gain of disorder (P = 0.0123);Gain of disorder (P = 0.0123);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519050; hg19: chr12-114836484;