14-75973291-C-T

Variant names:

• chr14-75973291-C-T
• rs2268625
• NM_003239.5:c.353-1573G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003239.5(TGFB3):​c.353-1573G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 152,176 control chromosomes in the GnomAD database, including 45,758 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 (45758 hom., cov: 33)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.93
• Publications: 15 publications found

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]

IFT43 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• short-rib thoracic dysplasia 18 with polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa 81

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003239.5. 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
	TGFB3	NM_003239.5	MANE Select	c.353-1573G>A		intron	N/A	NP_003230.1
	TGFB3	NM_001329939.2		c.353-1573G>A		intron	N/A	NP_001316868.1
	TGFB3	NM_001329938.2		c.353-1573G>A		intron	N/A	NP_001316867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.353-1573G>A		intron	N/A	ENSP00000238682.3
	TGFB3	ENST00000556285.1	TSL:1	c.353-1573G>A		intron	N/A	ENSP00000451110.1
	TGFB3	ENST00000556674.2	TSL:3	c.353-1573G>A		intron	N/A	ENSP00000502685.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117205 AN: 152058 Hom.: 45741 Cov.: 33

Gnomad AFR AF: 0.653

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: 0.866

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.783

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

GnomAD4 genome AF: 0.771 AC: 117263 AN: 152176 Hom.: 45758 Cov.: 33 AF XY: 0.771 AC XY: 57350 AN XY: 74398

African (AFR) AF: 0.652 AC: 27059 AN: 41478

American (AMR) AF: 0.770 AC: 11783 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2932 AN: 3472

East Asian (EAS) AF: 0.613 AC: 3170 AN: 5168

South Asian (SAS) AF: 0.823 AC: 3972 AN: 4828

European-Finnish (FIN) AF: 0.866 AC: 9173 AN: 10594

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56483 AN: 68014

Other (OTH) AF: 0.776 AC: 1643 AN: 2116

Alfa AF: 0.804 Hom.: 145085

Bravo AF: 0.761

Asia WGS AF: 0.722 AC: 2512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.11
DANN	Benign	0.73
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2268625; hg19: chr14-76439634;