rs11466414

Positions:

• chr14-75981507-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003239.5(TGFB3):​c.-614C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 169,424 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (210 hom., cov: 32)
  • Exomes 𝑓: 0.058 (32 hom.)
• Consequence: TGFB3 NM_003239.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-75981507-G-A is Benign according to our data. Variant chr14-75981507-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB3	NM_003239.5	c.-614C>T		5_prime_UTR_variant	1/7	ENST00000238682.8
TGFB3	NM_001329938.2	c.-614C>T		5_prime_UTR_variant	1/5
TGFB3	NM_001329939.2	c.-614C>T		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB3	ENST00000238682.8	c.-614C>T		5_prime_UTR_variant	1/7	1	NM_003239.5	P1
TGFB3	ENST00000556674.2	c.-614C>T		5_prime_UTR_variant	2/8	3		P1
TGFB3	ENST00000555193.1	c.-187-427C>T		intron_variant		4
IFT43	ENST00000555677.5	n.90-7378G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7098 AN: 152140 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.0549

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.0450

GnomAD4 exome AF: 0.0582 AC: 1000 AN: 17168 Hom.: 32 Cov.: 0 AF XY: 0.0567 AC XY: 512 AN XY: 9036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0762

Gnomad4 ASJ exome AF: 0.0500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0536

Gnomad4 NFE exome AF: 0.0649

Gnomad4 OTH exome AF: 0.0587

GnomAD4 genome AF: 0.0466 AC: 7097 AN: 152256 Hom.: 210 Cov.: 32 AF XY: 0.0460 AC XY: 3421 AN XY: 74434

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0470

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0416

Gnomad4 FIN AF: 0.0549

Gnomad4 NFE AF: 0.0659

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0622 Hom.: 88

Bravo AF: 0.0469

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cranioectodermal dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11466414; hg19: chr14-76447850;