rs147710408

chr12-114399559-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_181486.4(TBX5):c.316A>G(p.Ile106Val) variant causes a missense change. The variant allele was found at a frequency of 0.000721 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I106I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.92

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 -14 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.011402577).
• BP6: Variant 12-114399559-T-C is Benign according to our data. Variant chr12-114399559-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 213825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.316A>G	p.Ile106Val	missense_variant	4/9	ENST00000405440.7
TBX5	NM_000192.3	c.316A>G	p.Ile106Val	missense_variant	4/9
TBX5	NM_080717.4	c.166A>G	p.Ile56Val	missense_variant	3/8
TBX5	XM_017019912.2	c.364A>G	p.Ile122Val	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.316A>G	p.Ile106Val	missense_variant	4/9	1	NM_181486.4	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000990 AC: 249 AN: 251496 Hom.: 1 AF XY: 0.000905 AC XY: 123 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000713 AC: 1042 AN: 1461894 Hom.: 1 Cov.: 33 AF XY: 0.000707 AC XY: 514 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00968

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.000593

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74448

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000955 AC: 116

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holt-Oram syndrome Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	TBX5: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 01, 2017	- -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

TBX5-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2021

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2018

This alteration is classified as 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	0.087
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.081
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	-0.060	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0080	.;B;B;B
Vest4		0.50
MVP		0.93
MPC		0.67
ClinPred		0.013	T
GERP RS		4.7
Varity_R		0.27
gMVP		0.31

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: rs147710408; hg19: chr12-114837364; COSMIC: COSV100091609;