rs3917187

Variant names:

• chr14-75965793-T-C
• rs3917187
• NM_003239.5:c.647-98A>G

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.647-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 970,456 control chromosomes in the GnomAD database, including 259,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (34307 hom., cov: 31)
  • Exomes 𝑓: 0.74 (224765 hom.)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.53
• Publications: 21 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: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 14-75965793-T-C is Benign according to our data. Variant chr14-75965793-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.647-98A>G		intron_variant	Intron 3 of 6	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.647-98A>G		intron_variant	Intron 4 of 7		NP_001316868.1
TGFB3	NM_001329938.2	c.647-98A>G		intron_variant	Intron 3 of 4		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.647-98A>G		intron_variant	Intron 3 of 6	1	NM_003239.5	ENSP00000238682.3

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99244 AN: 151952 Hom.: 34307 Cov.: 31

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.737 AC: 603180 AN: 818386 Hom.: 224765 Cov.: 11 AF XY: 0.737 AC XY: 319056 AN XY: 433098

African (AFR) AF: 0.413 AC: 8682 AN: 21026

American (AMR) AF: 0.753 AC: 32746 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 16455 AN: 22134

East Asian (EAS) AF: 0.534 AC: 19472 AN: 36498

South Asian (SAS) AF: 0.697 AC: 50833 AN: 72942

European-Finnish (FIN) AF: 0.784 AC: 33765 AN: 43050

Middle Eastern (MID) AF: 0.685 AC: 3094 AN: 4518

European-Non Finnish (NFE) AF: 0.765 AC: 409785 AN: 535522

Other (OTH) AF: 0.723 AC: 28348 AN: 39202

GnomAD4 genome AF: 0.653 AC: 99253 AN: 152070 Hom.: 34307 Cov.: 31 AF XY: 0.655 AC XY: 48701 AN XY: 74342

African (AFR) AF: 0.414 AC: 17156 AN: 41452

American (AMR) AF: 0.701 AC: 10702 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2594 AN: 3472

East Asian (EAS) AF: 0.545 AC: 2817 AN: 5170

South Asian (SAS) AF: 0.690 AC: 3324 AN: 4818

European-Finnish (FIN) AF: 0.789 AC: 8352 AN: 10580

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51879 AN: 67986

Other (OTH) AF: 0.671 AC: 1419 AN: 2116

Alfa AF: 0.715 Hom.: 14845

Bravo AF: 0.638

Asia WGS AF: 0.598 AC: 2079 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 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.010
DANN	Benign	0.31
PhyloP100		-4.5
Mutation Taster		=99/1	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: rs3917187; hg19: chr14-76432136; COSMIC: COSV53170271; COSMIC: COSV53170271;