14-75978424-C-T

Variant names:

• chr14-75978424-C-T
• rs2268626
• NM_003239.5:c.352+2118G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003239.5(TGFB3):​c.352+2118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,164 control chromosomes in the GnomAD database, including 48,272 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48272 hom., cov: 32)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.352+2118G>A		intron_variant	Intron 1 of 6	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.352+2118G>A		intron_variant	Intron 2 of 7		NP_001316868.1
TGFB3	NM_001329938.2	c.352+2118G>A		intron_variant	Intron 1 of 4		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.352+2118G>A		intron_variant	Intron 1 of 6	1	NM_003239.5	ENSP00000238682.3
TGFB3	ENST00000556285.1	c.352+2118G>A		intron_variant	Intron 1 of 4	1		ENSP00000451110.1
TGFB3	ENST00000556674.2	c.352+2118G>A		intron_variant	Intron 2 of 7	3		ENSP00000502685.1
IFT43	ENST00000555677.5	n.90-10461C>T		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120928 AN: 152046 Hom.: 48249 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.771

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.795 AC: 121003 AN: 152164 Hom.: 48272 Cov.: 32 AF XY: 0.795 AC XY: 59131 AN XY: 74396

African (AFR) AF: 0.800 AC: 33171 AN: 41488

American (AMR) AF: 0.751 AC: 11487 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2827 AN: 3470

East Asian (EAS) AF: 0.669 AC: 3456 AN: 5166

South Asian (SAS) AF: 0.829 AC: 3992 AN: 4818

European-Finnish (FIN) AF: 0.856 AC: 9072 AN: 10602

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54459 AN: 68010

Other (OTH) AF: 0.768 AC: 1621 AN: 2112

Alfa AF: 0.796 Hom.: 87082

Bravo AF: 0.790

Asia WGS AF: 0.753 AC: 2618 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2268626; hg19: chr14-76444767;