rs3917192

Variant names:

• chr14-75965331-T-C
• rs3917192
• NM_003239.5:c.754+257A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003239.5(TGFB3):​c.754+257A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,240 control chromosomes in the GnomAD database, including 51,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.82 (51881 hom., cov: 33)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.30
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-75965331-T-C is Benign according to our data. Variant chr14-75965331-T-C is described in ClinVar as Benign. ClinVar VariationId is 683992.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.754+257A>G		intron_variant	Intron 4 of 6	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.754+257A>G		intron_variant	Intron 5 of 7		NP_001316868.1
TGFB3	NM_001329938.2	c.754+257A>G		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.754+257A>G		intron_variant	Intron 4 of 6	1	NM_003239.5	ENSP00000238682.3

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125343 AN: 152122 Hom.: 51840 Cov.: 33

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.862

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.829

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

GnomAD4 genome AF: 0.824 AC: 125433 AN: 152240 Hom.: 51881 Cov.: 33 AF XY: 0.822 AC XY: 61183 AN XY: 74436

African (AFR) AF: 0.824 AC: 34228 AN: 41540

American (AMR) AF: 0.800 AC: 12237 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 2994 AN: 3472

East Asian (EAS) AF: 0.584 AC: 3021 AN: 5172

South Asian (SAS) AF: 0.844 AC: 4076 AN: 4832

European-Finnish (FIN) AF: 0.854 AC: 9057 AN: 10604

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.838 AC: 57022 AN: 68006

Other (OTH) AF: 0.822 AC: 1737 AN: 2112

Alfa AF: 0.840 Hom.: 26898

Bravo AF: 0.820

Asia WGS AF: 0.730 AC: 2538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 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	-0.91
CADD	Benign	0.20
DANN	Benign	0.39
PhyloP100		-2.3
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: rs3917192; hg19: chr14-76431674;