rs2236017

chr12-114394705-C-Achr12-114394705-C-Gchr12-114394705-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181486.4(TBX5):c.663+36G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,612,396 control chromosomes in the GnomAD database, including 308,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25471 hom., cov: 31)
  • Exomes 𝑓: 0.62 (283352 hom.)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.956

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 (BayesDel_noAF=-0.83).
• BP6: Variant 12-114394705-C-A is Benign according to our data. Variant chr12-114394705-C-A is described in ClinVar as [Benign]. Clinvar id is 139592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114394705-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.663+36G>T		intron_variant		ENST00000405440.7
TBX5	NM_000192.3	c.663+36G>T		intron_variant
TBX5	NM_080717.4	c.513+36G>T		intron_variant
TBX5	XM_017019912.2	c.711+36G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.663+36G>T		intron_variant		1	NM_181486.4	P1
TBX5	ENST00000310346.8	c.663+36G>T		intron_variant		1		P1
TBX5	ENST00000349716.9	c.513+36G>T		intron_variant		1
TBX5	ENST00000526441.1	c.663+36G>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86344 AN: 151822 Hom.: 25451 Cov.: 31

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.589

GnomAD3 exomes AF: 0.619 AC: 155374 AN: 251088 Hom.: 49840 AF XY: 0.622 AC XY: 84362 AN XY: 135722

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.666

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.628

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.619 AC: 904338 AN: 1460456 Hom.: 283352 Cov.: 39 AF XY: 0.620 AC XY: 450819 AN XY: 726584

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.782

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.670

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.593

GnomAD4 genome AF: 0.569 AC: 86413 AN: 151940 Hom.: 25471 Cov.: 31 AF XY: 0.573 AC XY: 42549 AN XY: 74238

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.674

Gnomad4 FIN AF: 0.619

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.589

Alfa AF: 0.522 Hom.: 3754

Bravo AF: 0.566

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	Molecular Genetics and Enzymology, National Research Centre	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holt-Oram syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.18
Dann	Benign	0.60

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: rs2236017; hg19: chr12-114832510; COSMIC: COSV59860963; COSMIC: COSV59860963;