14-75975221-A-T

Variant names:

• chr14-75975221-A-T
• rs2300607
• NM_003239.5:c.353-3503T>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.353-3503T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,648 control chromosomes in the GnomAD database, including 35,195 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 0.67 (35195 hom., cov: 29)
• Consequence: TGFB3 NM_003239.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.597
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 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.353-3503T>A		intron	N/A	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.353-3503T>A		intron	N/A	NP_001316868.1	A5YM40
	TGFB3	NM_001329938.2		c.353-3503T>A		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.353-3503T>A		intron	N/A	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000556285.1	TSL:1	c.353-3503T>A		intron	N/A	ENSP00000451110.1	P10600-2
	TGFB3	ENST00000964917.1		c.515-3503T>A		intron	N/A	ENSP00000634976.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101067 AN: 151530 Hom.: 35193 Cov.: 29

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.667 AC: 101082 AN: 151648 Hom.: 35195 Cov.: 29 AF XY: 0.669 AC XY: 49542 AN XY: 74106

African (AFR) AF: 0.454 AC: 18747 AN: 41330

American (AMR) AF: 0.705 AC: 10754 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2594 AN: 3462

East Asian (EAS) AF: 0.581 AC: 2991 AN: 5144

South Asian (SAS) AF: 0.694 AC: 3319 AN: 4782

European-Finnish (FIN) AF: 0.804 AC: 8461 AN: 10522

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51793 AN: 67856

Other (OTH) AF: 0.672 AC: 1411 AN: 2100

Alfa AF: 0.718 Hom.: 5012

Bravo AF: 0.655

Asia WGS AF: 0.615 AC: 2139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.0
DANN	Benign	0.64
PhyloP100		0.60
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: rs2300607;

hg19: chr14-76441564;