14-75978126-T-C

Variant names:

• chr14-75978126-T-C
• rs3917158
• NM_003239.5:c.352+2416A>G

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+2416A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 151,952 control chromosomes in the GnomAD database, including 49,643 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 0.81 (49643 hom., cov: 30)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 14 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.824 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.352+2416A>G		intron	N/A	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.352+2416A>G		intron	N/A	NP_001316868.1	A5YM40
	TGFB3	NM_001329938.2		c.352+2416A>G		intron	N/A	NP_001316867.1	P10600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.352+2416A>G		intron	N/A	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000556285.1	TSL:1	c.352+2416A>G		intron	N/A	ENSP00000451110.1	P10600-2
	TGFB3	ENST00000964917.1		c.514+1790A>G		intron	N/A	ENSP00000634976.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122516 AN: 151834 Hom.: 49622 Cov.: 30

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.810

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

GnomAD4 genome AF: 0.807 AC: 122586 AN: 151952 Hom.: 49643 Cov.: 30 AF XY: 0.806 AC XY: 59860 AN XY: 74222

African (AFR) AF: 0.773 AC: 31995 AN: 41416

American (AMR) AF: 0.782 AC: 11949 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2972 AN: 3470

East Asian (EAS) AF: 0.644 AC: 3285 AN: 5104

South Asian (SAS) AF: 0.844 AC: 4053 AN: 4800

European-Finnish (FIN) AF: 0.865 AC: 9137 AN: 10568

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56445 AN: 68002

Other (OTH) AF: 0.806 AC: 1698 AN: 2108

Alfa AF: 0.828 Hom.: 26496

Bravo AF: 0.802

Asia WGS AF: 0.749 AC: 2604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.046
DANN	Benign	0.58
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3917158;

hg19: chr14-76444469;