rs77357563

chr12-114399544-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.17

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 Benign. Variant got -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_181486.4
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PrimateAI, PROVEAN, REVEL [when 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 579 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.331G>T	p.Asp111Tyr	missense_variant	4/9	ENST00000405440.7
TBX5	NM_000192.3	c.331G>T	p.Asp111Tyr	missense_variant	4/9
TBX5	NM_080717.4	c.181G>T	p.Asp61Tyr	missense_variant	3/8
TBX5	XM_017019912.2	c.379G>T	p.Asp127Tyr	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.331G>T	p.Asp111Tyr	missense_variant	4/9	1	NM_181486.4	P1

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 152122 Hom.: 1 Cov.: 32

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.: 4 AF XY: 0.00325 AC XY: 442 AN XY: 135920

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.: 14 Cov.: 33 AF XY: 0.00411 AC XY: 2987 AN XY: 727244

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.: 1 Cov.: 32 AF XY: 0.00369 AC XY: 275 AN XY: 74430

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.: 5

Bravo AF: 0.00441

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00340 AC: 413

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TBX5: PP3, BS1, BS2 -

Holt-Oram syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	-	- -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

TBX5-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

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	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
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	T
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

Other links and lift over

dbSNP: rs77357563; hg19: chr12-114837349;