rs143068551

Positions:

chr12-114355974-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_181486.4(TBX5):c.1115C>T(p.Ser372Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19646144).

BP6

Variant 12-114355974-G-A is Benign according to our data. Variant chr12-114355974-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477655.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	9/9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	9/9		NP_000183.2	Q99593-1
TBX5	NM_080717.4 linkuse as main transcript	c.965C>T	p.Ser322Leu	missense_variant	8/8		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 linkuse as main transcript	c.1163C>T	p.Ser388Leu	missense_variant	9/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBX5	ENST00000405440.7 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	9/9	1	NM_181486.4	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	9/9	1		ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9 linkuse as main transcript	c.965C>T	p.Ser322Leu	missense_variant	8/8	1		ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251324

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000311

AC:

455

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

217

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000368

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000309

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

TBX5-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

The TBX5 c.1115C>T variant is predicted to result in the amino acid substitution p.Ser372Leu. This variant was reported as an inherited variant in an individual with bicuspid aortic valve (Table 1. Bonachea et al. 2014. PubMed ID: 25260786), in two individuals with paroxysmal atrial fibrillation (AF; Table 3. Ma et al. 2016. PubMed ID: 26762269), and in a fetus with congenital diaphragmatic hernia (Table 1. Kammoun et al. 2018. PubMed ID: 29966037). This variant was also reported as a maternally-inherited variant in an individual with tetralogy of fallot, ostium secundum atrial septal defect, and progressive arrhythmic changes on ECG whose mother was asymptomatic, but upon clinical examination revealed frequent ventricular extrasystoles and an atrial septal aneurysm (Baban et al. 2014. PubMed ID: 25263169). Functional studies of this variant revealed it led to an increase in protein function (Baban et al. 2014. PubMed ID: 25263169) and enhanced expression of AF-related proteins ANP and Cx40 (Ma et al. 2016. PubMed ID: 26762269). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26219450, 25260786, 26762269, 29966037, 34426522, 25263169) -

Holt-Oram syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 17, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Aortic valve disease 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

.;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.088

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.86

.;P;P

Vest4

0.61

MVP

0.74

MPC

0.13

ClinPred

0.070

GERP RS

5.3

Varity_R

0.23

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over