12-114355435-C-T

Position:

• chr12-114355435-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.*97G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,452,266 control chromosomes in the GnomAD database, including 352,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34304 hom., cov: 32)
  • Exomes 𝑓: 0.69 (317962 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.967

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=-0.7).
• BP6: Variant 12-114355435-C-T is Benign according to our data. Variant chr12-114355435-C-T is described in ClinVar as [Benign]. Clinvar id is 307300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114355435-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.*97G>A		3_prime_UTR_variant	9/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.*97G>A		3_prime_UTR_variant	9/9		NP_000183.2
TBX5	NM_080717.4	c.*97G>A		3_prime_UTR_variant	8/8		NP_542448.1
TBX5	XM_017019912.2	c.*97G>A		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.*97G>A		3_prime_UTR_variant	9/9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346	c.*97G>A		3_prime_UTR_variant	9/9	1		ENSP00000309913.4
TBX5	ENST00000349716	c.*97G>A		3_prime_UTR_variant	8/8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101189 AN: 151862 Hom.: 34283 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.611 AC: 100725 AN: 164920 Hom.: 32173 AF XY: 0.618 AC XY: 54905 AN XY: 88902

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.694 AC: 901902 AN: 1300284 Hom.: 317962 Cov.: 20 AF XY: 0.690 AC XY: 447237 AN XY: 648084

Gnomad4 AFR exome AF: 0.668

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.610

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.666 AC: 101249 AN: 151982 Hom.: 34304 Cov.: 32 AF XY: 0.659 AC XY: 48937 AN XY: 74278

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.604

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.726

Gnomad4 OTH AF: 0.643

Alfa AF: 0.693 Hom.: 72116

Bravo AF: 0.654

Asia WGS AF: 0.465 AC: 1619 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holt-Oram syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.70
CADD	Benign	8.4
DANN	Benign	0.85

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: rs883079; hg19: chr12-114793240;