14-75958704-TAAAA-TAA

Variant names:

• chr14-75958704-TAA-T
• rs199646113
• NM_003239.5:c.*481_*482delTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_003239.5(TGFB3):​c.*481_*482delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 172,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.055 (0 hom.)
• Consequence: TGFB3 NM_003239.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68

Genes affected

TGFB3 (HGNC:11769): (transforming growth factor beta 3) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]

IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.*481_*482delTT		3_prime_UTR_variant	Exon 7 of 7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.*481_*482delTT		3_prime_UTR_variant	Exon 8 of 8		NP_001316868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682	c.*481_*482delTT		3_prime_UTR_variant	Exon 7 of 7	1	NM_003239.5	ENSP00000238682.3
TGFB3	ENST00000556674	c.*481_*482delTT		3_prime_UTR_variant	Exon 8 of 8	3		ENSP00000502685.1
TGFB3	ENST00000554980.5	n.2101_2102delTT		non_coding_transcript_exon_variant	Exon 4 of 4	2
IFT43	ENST00000555677.5	n.90-30166_90-30165delAA		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 27 AN: 140656 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000143

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000124

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0546 AC: 1758 AN: 32176 Hom.: 0 AF XY: 0.0554 AC XY: 915 AN XY: 16502

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.0438

Gnomad4 EAS exome AF: 0.0631

Gnomad4 SAS exome AF: 0.0579

Gnomad4 FIN exome AF: 0.0539

Gnomad4 NFE exome AF: 0.0537

Gnomad4 OTH exome AF: 0.0481

GnomAD4 genome AF: 0.000192 AC: 27 AN: 140686 Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 15 AN XY: 68256

Gnomad4 AFR AF: 0.000183

Gnomad4 AMR AF: 0.000143

Gnomad4 ASJ AF: 0.000304

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000125

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs199646113; hg19: chr14-76425047;