rs3917200

Positions:

• chr14-75963525-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003239.5(TGFB3):​c.755-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,613,214 control chromosomes in the GnomAD database, including 8,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.14 (2283 hom., cov: 32)
  • Exomes 𝑓: 0.084 (6336 hom.)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.129

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 -14 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-75963525-A-G is Benign according to our data. Variant chr14-75963525-A-G is described in ClinVar as [Benign]. Clinvar id is 674788.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-75963525-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB3	NM_003239.5	c.755-38T>C		intron_variant		ENST00000238682.8
TGFB3	NM_001329938.2	c.755-38T>C		intron_variant
TGFB3	NM_001329939.2	c.755-38T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB3	ENST00000238682.8	c.755-38T>C		intron_variant		1	NM_003239.5	P1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20883 AN: 152044 Hom.: 2264 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.0921 AC: 23034 AN: 250042 Hom.: 1538 AF XY: 0.0911 AC XY: 12312 AN XY: 135210

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.0686

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0296

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0763

Gnomad OTH exome AF: 0.0924

GnomAD4 exome AF: 0.0839 AC: 122611 AN: 1461052 Hom.: 6336 Cov.: 33 AF XY: 0.0844 AC XY: 61321 AN XY: 726862

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.0726

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.0562

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0699

Gnomad4 NFE exome AF: 0.0754

Gnomad4 OTH exome AF: 0.0957

GnomAD4 genome AF: 0.138 AC: 20945 AN: 152162 Hom.: 2283 Cov.: 32 AF XY: 0.134 AC XY: 9982 AN XY: 74404

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.0936

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.0398

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0633

Gnomad4 NFE AF: 0.0741

Gnomad4 OTH AF: 0.131

Alfa AF: 0.123 Hom.: 432

Bravo AF: 0.146

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.8
DANN	Benign	0.53
BranchPoint Hunter		2.0

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: rs3917200; hg19: chr14-76429868; COSMIC: COSV53170002; COSMIC: COSV53170002;