12-114355435-C-G

Variant names:

• chr12-114355435-C-G
• rs883079
• NM_181486.4:c.*97G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_181486.4(TBX5):​c.*97G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,454,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.967
• Publications: 70 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.*97G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.*97G>C		3_prime_UTR_variant	Exon 9 of 9		NP_000183.2
TBX5	NM_080717.4	c.*97G>C		3_prime_UTR_variant	Exon 8 of 8		NP_542448.1
TBX5	XM_017019912.2	c.*97G>C		3_prime_UTR_variant	Exon 9 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.*97G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.*97G>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.*97G>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000182 AC: 3 AN: 164920 AF XY: 0.0000112

Gnomad AFR exome AF: 0.000362

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 16 AN: 1302236 Hom.: 0 Cov.: 20 AF XY: 0.00000770 AC XY: 5 AN XY: 649010

African (AFR) AF: 0.000500 AC: 15 AN: 30002

American (AMR) AF: 0.00 AC: 0 AN: 36456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24624

East Asian (EAS) AF: 0.00 AC: 0 AN: 36532

South Asian (SAS) AF: 0.00 AC: 0 AN: 77520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46578

Middle Eastern (MID) AF: 0.000200 AC: 1 AN: 4998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 990516

Other (OTH) AF: 0.00 AC: 0 AN: 55010

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74194

African (AFR) AF: 0.000218 AC: 9 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 156063

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.79
PhyloP100		-0.97

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: rs883079; hg19: chr12-114793240;