chr12-114408030-C-A

Variant names:

• chr12-114408030-C-A
• rs186472610
• ENST00000310346.8:c.-255G>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000192.3(TBX5):​c.-255G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 985,440 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: TBX5 NM_000192.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

TBX5-AS1 (HGNC:27402): (TBX5 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000991 (151/152324) while in subpopulation NFE AF= 0.0015 (102/68034). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_000192.3	c.-255G>T		5_prime_UTR_variant	Exon 1 of 9		NP_000183.2
TBX5	NM_080717.4	c.-220G>T		upstream_gene_variant			NP_542448.1
TBX5	XM_017019912.2	c.-1692G>T		upstream_gene_variant			XP_016875401.1
TBX5-AS1	NR_038440.1	n.-165C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000310346.8	c.-255G>T		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.-220G>T		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000337723.5
TBX5-AS1	ENST00000528549.3	n.-104C>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00202 AC: 1687 AN: 833116 Hom.: 1 Cov.: 29 AF XY: 0.00214 AC XY: 824 AN XY: 384722

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000790

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74482

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holt-Oram syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186472610; hg19: chr12-114845835;