14-75958704-TAAAA-TAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003239.5(TGFB3):​c.*481_*482dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 174,238 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 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (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.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000185 (26/140872) while in subpopulation AFR AF= 0.000627 (24/38268). AF 95% confidence interval is 0.000432. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.*481_*482dupTT		3_prime_UTR_variant	Exon 7 of 7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.*481_*482dupTT		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_*482dupTT		3_prime_UTR_variant	Exon 7 of 7	1	NM_003239.5	ENSP00000238682.3
TGFB3	ENST00000556674	c.*481_*482dupTT		3_prime_UTR_variant	Exon 8 of 8	3		ENSP00000502685.1
TGFB3	ENST00000554980.5	n.2101_2102dupTT		non_coding_transcript_exon_variant	Exon 4 of 4	2
IFT43	ENST00000555677.5	n.90-30166_90-30165dupAA		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 26 AN: 140842 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00135 AC: 45 AN: 33366 Hom.: 0 Cov.: 0 AF XY: 0.00129 AC XY: 22 AN XY: 17092

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00312

Gnomad4 EAS exome AF: 0.000903

Gnomad4 SAS exome AF: 0.00221

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000185 AC: 26 AN: 140872 Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 8 AN XY: 68346

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.0000713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000115

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;