rs1555226019

Variant names:

• chr12-114394847-A-C
• rs1555226019
• NM_181486.4:c.557T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-114394847-A-C
• chr12-114394847-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_181486.4(TBX5):​c.557T>G​(p.Val186Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.25

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.557T>G	p.Val186Gly	missense_variant	Exon 6 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.557T>G	p.Val186Gly	missense_variant	Exon 6 of 9		NP_000183.2
TBX5	NM_080717.4	c.407T>G	p.Val136Gly	missense_variant	Exon 5 of 8		NP_542448.1
TBX5	XM_017019912.2	c.605T>G	p.Val202Gly	missense_variant	Exon 6 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.557T>G	p.Val186Gly	missense_variant	Exon 6 of 9	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holt-Oram syndrome Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBX5 NM_000192.3 p.Val186Gly (c.557T>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aortic valve disease 2 Uncertain:1

Nov 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with glycine at codon 186 of the TBX5 protein (p.Val186Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TBX5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.4	.;M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.62
MutPred		0.70		.;Gain of catalytic residue at R182 (P = 0);Gain of catalytic residue at R182 (P = 0);Gain of catalytic residue at R182 (P = 0);
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555226019; hg19: chr12-114832652;