chr12-114399566-G-A

Position:

• chr12-114399566-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_181486.4(TBX5):​c.309C>T​(p.Leu103Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00742 in 1,614,098 control chromosomes in the GnomAD database, including 794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (402 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (392 hom.)
• Consequence: TBX5 NM_181486.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.153

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-114399566-G-A is Benign according to our data. Variant chr12-114399566-G-A is described in ClinVar as [Benign]. Clinvar id is 213815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114399566-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.309C>T	p.Leu103Leu	synonymous_variant	4/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.309C>T	p.Leu103Leu	synonymous_variant	4/9		NP_000183.2
TBX5	NM_080717.4	c.159C>T	p.Leu53Leu	synonymous_variant	3/8		NP_542448.1
TBX5	XM_017019912.2	c.357C>T	p.Leu119Leu	synonymous_variant	4/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.309C>T	p.Leu103Leu	synonymous_variant	4/9	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6018 AN: 152090 Hom.: 397 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0105 AC: 2644 AN: 251494 Hom.: 167 AF XY: 0.00731 AC XY: 994 AN XY: 135922

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00406 AC: 5936 AN: 1461890 Hom.: 392 Cov.: 33 AF XY: 0.00345 AC XY: 2510 AN XY: 727248

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.0397 AC: 6043 AN: 152208 Hom.: 402 Cov.: 32 AF XY: 0.0386 AC XY: 2873 AN XY: 74442

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0238 Hom.: 124

Bravo AF: 0.0463

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2016	Variant summary: The TBX5 c.309C>T (p.Leu103Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. This variant was found in 1592/121410 control chromosomes (111 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1429258 (1487/10404). This frequency significantly exceeds the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000013), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in multiple affected individuals as a polymorphism. Some patient also carried a pathogenic variant, further supporting the benign classification of this variant. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -
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. -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.4
DANN	Benign	0.92

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: rs28730763; hg19: chr12-114837371; COSMIC: COSV59861258;