rs2268624

chr14-75973002-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003239.5(TGFB3):c.353-1284C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 152,150 control chromosomes in the GnomAD database, including 45,853 homozygotes. 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 0.77 (45853 hom., cov: 32)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB3	NM_003239.5	c.353-1284C>G		intron_variant		ENST00000238682.8
TGFB3	NM_001329938.2	c.353-1284C>G		intron_variant
TGFB3	NM_001329939.2	c.353-1284C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB3	ENST00000238682.8	c.353-1284C>G		intron_variant		1	NM_003239.5	P1
TGFB3	ENST00000556285.1	c.353-1284C>G		intron_variant		1
TGFB3	ENST00000556674.2	c.353-1284C>G		intron_variant		3		P1
IFT43	ENST00000555677.5	n.90-15883G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117325 AN: 152034 Hom.: 45836 Cov.: 32

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.784

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.772 AC: 117385 AN: 152150 Hom.: 45853 Cov.: 32 AF XY: 0.772 AC XY: 57414 AN XY: 74390

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.844

Gnomad4 EAS AF: 0.613

Gnomad4 SAS AF: 0.823

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.779

Alfa AF: 0.803 Hom.: 6176

Bravo AF: 0.762

Asia WGS AF: 0.723 AC: 2515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.9
Dann	Benign	0.45

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: rs2268624; hg19: chr14-76439345;