chr12-114354431-T-C

Position:

• chr12-114354431-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.*1101A>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 0.801 in 151,976 control chromosomes in the GnomAD database, including 48,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48945 hom., cov: 31)
  • Exomes 𝑓: 1.0 (2 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.26

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=-0.91).
• BP6: Variant 12-114354431-T-C is Benign according to our data. Variant chr12-114354431-T-C is described in ClinVar as [Benign]. Clinvar id is 307275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.*1101A>G		3_prime_UTR_variant	9/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.*1101A>G		3_prime_UTR_variant	9/9		NP_000183.2
TBX5	NM_080717.4	c.*1101A>G		3_prime_UTR_variant	8/8		NP_542448.1
TBX5	XM_017019912.2	c.*1101A>G		3_prime_UTR_variant	9/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.*1101A>G		3_prime_UTR_variant	9/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.*1101A>G		3_prime_UTR_variant	9/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.*1101A>G		3_prime_UTR_variant	8/8	1		ENSP00000337723

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121594 AN: 151854 Hom.: 48911 Cov.: 31

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.788

GnomAD4 exome AF: 1.00 AC: 4 AN: 4 Hom.: 2 Cov.: 0 AF XY: 1.00 AC XY: 4 AN XY: 4

Gnomad4 FIN exome AF: 1.00

GnomAD4 genome AF: 0.801 AC: 121672 AN: 151972 Hom.: 48945 Cov.: 31 AF XY: 0.797 AC XY: 59201 AN XY: 74246

Gnomad4 AFR AF: 0.809

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.783

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.762

Gnomad4 FIN AF: 0.777

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.789

Alfa AF: 0.800 Hom.: 66799

Bravo AF: 0.795

Asia WGS AF: 0.805 AC: 2802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	This variant is associated with the following publications: (PMID: 28761722) -

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	-0.91
CADD	Benign	0.40
DANN	Benign	0.41

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: rs6489956; hg19: chr12-114792236;