12-114399544-C-A

Position:

chr12-114399544-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_181486.4(TBX5):c.331G>T(p.Asp111Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00418 in 1,614,124 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 14 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.17

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 -17 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

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.061571628).

BP6

Variant 12-114399544-C-A is Benign according to our data. Variant chr12-114399544-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 213813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114399544-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0038 (578/152240) while in subpopulation AMR AF= 0.0107 (163/15284). AF 95% confidence interval is 0.00933. There are 1 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 578 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBX5	NM_181486.4 linkuse as main transcript	c.331G>T	p.Asp111Tyr	missense_variant	4/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3 linkuse as main transcript	c.331G>T	p.Asp111Tyr	missense_variant	4/9		NP_000183.2
TBX5	NM_080717.4 linkuse as main transcript	c.181G>T	p.Asp61Tyr	missense_variant	3/8		NP_542448.1
TBX5	XM_017019912.2 linkuse as main transcript	c.379G>T	p.Asp127Tyr	missense_variant	4/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7 linkuse as main transcript	c.331G>T	p.Asp111Tyr	missense_variant	4/9	1	NM_181486.4	ENSP00000384152	P1	Q99593-1

Frequencies

GnomAD3 genomes

AF:

0.00381

AC:

579

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00334

AC:

840

AN:

251494

Hom.:

AF XY:

0.00325

AC XY:

442

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00477

Gnomad OTH exome

AF:

0.00521

GnomAD4 exome

AF:

0.00422

AC:

6173

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

2987

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00682

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00492

Gnomad4 OTH exome

AF:

0.00454

GnomAD4 genome

AF:

0.00380

AC:

578

AN:

152240

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

275

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00523

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00458

Hom.:

Bravo

AF:

0.00441

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00340

AC:

413

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TBX5: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2019	This variant is associated with the following publications: (PMID: 22011241, 16376438, 19429598, 28251916, 28074886, 30639323) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holt-Oram syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

TBX5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Aortic valve disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.062

T;T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.9

.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.7

D;D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.94

MVP

0.97

MPC

2.0

ClinPred

0.053

GERP RS

4.7

Varity_R

0.91

gMVP

0.79

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

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