rs10850326

Positions:

• chr12-114355492-T-C

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.*40A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,609,080 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (327 hom., cov: 33)
  • Exomes 𝑓: 0.016 (2341 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.30

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=-0.77).
• BP6: Variant 12-114355492-T-C is Benign according to our data. Variant chr12-114355492-T-C is described in ClinVar as [Benign]. Clinvar id is 255489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114355492-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.*40A>G		3_prime_UTR_variant	9/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.*40A>G		3_prime_UTR_variant	9/9		NP_000183.2
TBX5	NM_080717.4	c.*40A>G		3_prime_UTR_variant	8/8		NP_542448.1
TBX5	XM_017019912.2	c.*40A>G		3_prime_UTR_variant	9/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440	c.*40A>G		3_prime_UTR_variant	9/9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346	c.*40A>G		3_prime_UTR_variant	9/9	1		ENSP00000309913.4
TBX5	ENST00000349716	c.*40A>G		3_prime_UTR_variant	8/8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2637 AN: 152216 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00411

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0347 AC: 8526 AN: 245914 Hom.: 1085 AF XY: 0.0348 AC XY: 4646 AN XY: 133658

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.341

Gnomad SAS exome AF: 0.0505

Gnomad FIN exome AF: 0.00276

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0160 AC: 23289 AN: 1456748 Hom.: 2341 Cov.: 32 AF XY: 0.0169 AC XY: 12277 AN XY: 724828

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.0511

Gnomad4 FIN exome AF: 0.00392

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0173 AC: 2639 AN: 152332 Hom.: 327 Cov.: 33 AF XY: 0.0204 AC XY: 1518 AN XY: 74478

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00624 Hom.: 9

Bravo AF: 0.0183

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Holt-Oram syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.92
DANN	Benign	0.76

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: rs10850326; hg19: chr12-114793297; COSMIC: COSV59861938;