rs1057519050

Variant names:

• chr12-114398679-A-C
• rs1057519050
• NM_181486.4:c.404T>G

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 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
• 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 rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 9		NP_000183.2
TBX5	NM_080717.4	c.254T>G	p.Leu85Arg	missense_variant	Exon 4 of 8		NP_542448.1
TBX5	XM_017019912.2	c.452T>G	p.Leu151Arg	missense_variant	Exon 5 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 9	1	NM_181486.4	ENSP00000384152.3

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

Jun 01, 2016

Human Genetics and Genome Research Institute, National Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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
DEOGEN2	Pathogenic	0.87	.;D;D;.
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
MutationAssessor	Pathogenic	2.9	.;M;M;M
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;