rs11466414

Variant names:

• chr14-75981507-G-A
• rs11466414
• NM_003239.5:c.-614C>T

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.-614C>T variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.06
• Publications: 16 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=-0.55).
• BP6: Variant 14-75981507-G-A is Benign according to our data. Variant chr14-75981507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003239.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	NM_003239.5	MANE Select	c.-614C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_003230.1
	TGFB3	NM_003239.5	MANE Select	c.-614C>T		5_prime_UTR	Exon 1 of 7	NP_003230.1
	TGFB3	NM_001329939.2		c.-614C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001316868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.-614C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000238682.3
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.-614C>T		5_prime_UTR	Exon 1 of 7	ENSP00000238682.3
	TGFB3	ENST00000556674.2	TSL:3	c.-614C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000502685.1

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

African (AFR) AF: 0.00 AC: 0 AN: 130

American (AMR) AF: 0.0762 AC: 218 AN: 2860

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 7 AN: 140

East Asian (EAS) AF: 0.00 AC: 0 AN: 752

South Asian (SAS) AF: 0.0344 AC: 85 AN: 2468

European-Finnish (FIN) AF: 0.0536 AC: 30 AN: 560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.0649 AC: 620 AN: 9546

Other (OTH) AF: 0.0587 AC: 40 AN: 682

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

African (AFR) AF: 0.0130 AC: 541 AN: 41562

American (AMR) AF: 0.0664 AC: 1017 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.0416 AC: 201 AN: 4830

European-Finnish (FIN) AF: 0.0549 AC: 581 AN: 10582

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0659 AC: 4479 AN: 68012

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

Alfa AF: 0.0508 Hom.: 136

Bravo AF: 0.0469

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cranioectodermal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		2.1
PromoterAI		-0.15	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11466414; hg19: chr14-76447850;