rs28730762

chr12-114366149-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000526441.1(TBX5):c.998C>T(p.Pro333Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00881 in 1,610,238 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (69 hom.)
• Consequence: TBX5 ENST00000526441.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0580

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057828724).
• BP6: Variant 12-114366149-G-A is Benign according to our data. Variant chr12-114366149-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114366149-G-A is described in Lovd as [Benign]. Variant chr12-114366149-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00664 (1011/152264) while in subpopulation NFE AF= 0.0107 (726/68018). AF 95% confidence interval is 0.01. There are 5 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.982+16C>T		intron_variant		ENST00000405440.7
TBX5	NM_000192.3	c.982+16C>T		intron_variant
TBX5	NM_080717.4	c.832+16C>T		intron_variant
TBX5	XM_017019912.2	c.1030+16C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000526441.1	c.998C>T	p.Pro333Leu	missense_variant	7/7	1
TBX5	ENST00000405440.7	c.982+16C>T		intron_variant		1	NM_181486.4	P1
TBX5	ENST00000310346.8	c.982+16C>T		intron_variant		1		P1
TBX5	ENST00000349716.9	c.832+16C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00545 AC: 1370 AN: 251348 Hom.: 8 AF XY: 0.00561 AC XY: 762 AN XY: 135846

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00904

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00903 AC: 13168 AN: 1457974 Hom.: 69 Cov.: 31 AF XY: 0.00865 AC XY: 6275 AN XY: 725484

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000789

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00753

GnomAD4 genome AF: 0.00664 AC: 1011 AN: 152264 Hom.: 5 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74460

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00866 Hom.: 12

Bravo AF: 0.00675

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00533 AC: 647

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TBX5: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	1.3
Dann	Benign	0.57
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.23
MVP		0.61
ClinPred		0.015	T
GERP RS		2.6

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: rs28730762; hg19: chr12-114803954;