14-75958363-A-G

Position:

• chr14-75958363-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003239.5(TGFB3):​c.*824T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 152,866 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (0 hom.)
• Consequence: TGFB3 NM_003239.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.152

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=-0.68).
• BP6: Variant 14-75958363-A-G is Benign according to our data. Variant chr14-75958363-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1218765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00562 (856/152304) while in subpopulation SAS AF= 0.0267 (129/4828). AF 95% confidence interval is 0.023. There are 14 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 856 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.*824T>C		3_prime_UTR_variant	7/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.*824T>C		3_prime_UTR_variant	8/8		NP_001316868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.*824T>C		3_prime_UTR_variant	7/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3	ENST00000556674.2	c.*824T>C		3_prime_UTR_variant	8/8	3		ENSP00000502685	P1
TGFB3	ENST00000554980.5	n.2444T>C		non_coding_transcript_exon_variant	4/4	2
IFT43	ENST00000555677.5	n.90-30522A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152186 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00890 AC: 5 AN: 562 Hom.: 0 Cov.: 0 AF XY: 0.00909 AC XY: 3 AN XY: 330

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152304 Hom.: 14 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74480

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00541

Asia WGS AF: 0.0230 AC: 78 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.83

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: rs116586110; hg19: chr14-76424706;