14-75958521-T-C

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.*666A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 155,260 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (142 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (0 hom.)
• Consequence: TGFB3 NM_003239.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-75958521-T-C is Benign according to our data. Variant chr14-75958521-T-C is described in ClinVar as [Benign]. Clinvar id is 1239029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB3	NM_003239.5	c.*666A>G		3_prime_UTR_variant	7/7	ENST00000238682.8
TGFB3	NM_001329939.2	c.*666A>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB3	ENST00000238682.8	c.*666A>G		3_prime_UTR_variant	7/7	1	NM_003239.5	P1
TGFB3	ENST00000556674.2	c.*666A>G		3_prime_UTR_variant	8/8	3		P1
TGFB3	ENST00000554980.5	n.2286A>G		non_coding_transcript_exon_variant	4/4	2
IFT43	ENST00000555677.5	n.90-30364T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3605 AN: 152132 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00399 AC: 12 AN: 3010 Hom.: 0 Cov.: 0 AF XY: 0.00685 AC XY: 11 AN XY: 1606

Gnomad4 AFR exome AF: 0.0714

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0222

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0238 AC: 3630 AN: 152250 Hom.: 142 Cov.: 32 AF XY: 0.0233 AC XY: 1735 AN XY: 74432

Gnomad4 AFR AF: 0.0794

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00575 Hom.: 22

Bravo AF: 0.0262

Asia WGS AF: 0.0290 AC: 99 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 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.8
Dann	Benign	0.52

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: rs4252348; hg19: chr14-76424864;