rs6489957

Variant names:

• chr12-114355808-G-A
• rs6489957
• NM_181486.4:c.1281C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181486.4(TBX5):​c.1281C>T​(p.Ser427Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,076 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (60 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (57 hom.)
• Consequence: TBX5 NM_181486.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.488
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-114355808-G-A is Benign according to our data. Variant chr12-114355808-G-A is described in ClinVar as Benign. ClinVar VariationId is 255491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.488 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	NM_181486.4	MANE Select	c.1281C>T	p.Ser427Ser	synonymous	Exon 9 of 9	NP_852259.1
	TBX5	NM_000192.3		c.1281C>T	p.Ser427Ser	synonymous	Exon 9 of 9	NP_000183.2
	TBX5	NM_080717.4		c.1131C>T	p.Ser377Ser	synonymous	Exon 8 of 8	NP_542448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.1281C>T	p.Ser427Ser	synonymous	Exon 9 of 9	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.1281C>T	p.Ser427Ser	synonymous	Exon 9 of 9	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.1131C>T	p.Ser377Ser	synonymous	Exon 8 of 8	ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2467 AN: 152168 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00437 AC: 1097 AN: 250758 AF XY: 0.00321

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00163 AC: 2386 AN: 1461790 Hom.: 57 Cov.: 33 AF XY: 0.00136 AC XY: 986 AN XY: 727210

African (AFR) AF: 0.0574 AC: 1921 AN: 33480

American (AMR) AF: 0.00340 AC: 152 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111998

Other (OTH) AF: 0.00354 AC: 214 AN: 60392

GnomAD4 genome AF: 0.0163 AC: 2479 AN: 152286 Hom.: 60 Cov.: 33 AF XY: 0.0156 AC XY: 1165 AN XY: 74450

African (AFR) AF: 0.0563 AC: 2338 AN: 41550

American (AMR) AF: 0.00686 AC: 105 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0154 Hom.: 38

Bravo AF: 0.0190

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Aortic valve disease 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Holt-Oram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.13
DANN	Benign	0.89
PhyloP100		-0.49
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs6489957; hg19: chr12-114793613; COSMIC: COSV59866470;