Variant 12-114408224-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000310346.8(TBX5):c.-449G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 985,124 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

TBX5
ENST00000310346.8 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0190

Variant links:

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 links:

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

TBX5-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 12-114408224-C-G is Benign according to our data. Variant chr12-114408224-C-G is described in ClinVar as [Benign]. Clinvar id is 307317.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00423 (644/152226) while in subpopulation AFR AF= 0.0146 (608/41522). AF 95% confidence interval is 0.0137. There are 4 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 644 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5-AS1	NR_038440.1 linkuse as main transcript	n.30C>G		non_coding_transcript_exon_variant	1/3
TBX5	NM_000192.3 linkuse as main transcript	c.-449G>C		5_prime_UTR_variant	1/9		NP_000183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5-AS1	ENST00000528549.3 linkuse as main transcript	n.91C>G		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000525

AC:

437

AN:

832898

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

198

AN XY:

384632

show subpopulations

Gnomad4 AFR exome

AF:

0.0163

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000189

Gnomad4 OTH exome

AF:

0.000953

GnomAD4 genome

AF:

0.00423

AC:

644

AN:

152226

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

319

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00499

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

-0.79

CADD

Benign

6.8

DANN

Benign

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over