rs3917200

Variant names:

• chr14-75963525-A-G
• rs3917200
• NM_003239.5:c.755-38T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.129
• Publications: 23 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId is 674788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.755-38T>C		intron_variant	Intron 4 of 6	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.755-38T>C		intron_variant	Intron 5 of 7		NP_001316868.1
TGFB3	NM_001329938.2	c.755-38T>C		intron_variant	Intron 4 of 4		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.755-38T>C		intron_variant	Intron 4 of 6	1	NM_003239.5	ENSP00000238682.3

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

GnomAD2 exomes AF: 0.0921 AC: 23034 AN: 250042 AF XY: 0.0911

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 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

African (AFR) AF: 0.308 AC: 10311 AN: 33466

American (AMR) AF: 0.0726 AC: 3246 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3026 AN: 26134

East Asian (EAS) AF: 0.0562 AC: 2232 AN: 39700

South Asian (SAS) AF: 0.115 AC: 9960 AN: 86240

European-Finnish (FIN) AF: 0.0699 AC: 3702 AN: 52988

Middle Eastern (MID) AF: 0.0947 AC: 532 AN: 5620

European-Non Finnish (NFE) AF: 0.0754 AC: 83823 AN: 1111822

Other (OTH) AF: 0.0957 AC: 5779 AN: 60358

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

African (AFR) AF: 0.297 AC: 12324 AN: 41464

American (AMR) AF: 0.0936 AC: 1433 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3472

East Asian (EAS) AF: 0.0398 AC: 206 AN: 5182

South Asian (SAS) AF: 0.114 AC: 550 AN: 4824

European-Finnish (FIN) AF: 0.0633 AC: 672 AN: 10610

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0741 AC: 5038 AN: 67992

Other (OTH) AF: 0.131 AC: 277 AN: 2110

Alfa AF: 0.127 Hom.: 467

Bravo AF: 0.146

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.13
BranchPoint Hunter		2.0
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: rs3917200; hg19: chr14-76429868; COSMIC: COSV53170002; COSMIC: COSV53170002;