rs3917200

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003239.5(TGFB3):c.755-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,613,214 control chromosomes in the GnomAD database, including 8,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.14 ( 2283 hom., cov: 32)

Exomes 𝑓: 0.084 ( 6336 hom. )

Consequence

TGFB3
NM_003239.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.129

Publications

23 publications found

Variant links:

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]

TGFB3 links:

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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

IFT43 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 14-75963525-A-G is Benign according to our data. Variant chr14-75963525-A-G is described in ClinVar as Benign. ClinVar VariationId is 674788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFB3	NM_003239.5	MANE Select	c.755-38T>C	intron	N/A	NP_003230.1	A5YM40
TGFB3	NM_001329939.2		c.755-38T>C	intron	N/A	NP_001316868.1	A5YM40
TGFB3	NM_001329938.2		c.755-38T>C	intron	N/A	NP_001316867.1	P10600-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.755-38T>C	intron	N/A	ENSP00000238682.3	P10600-1
TGFB3	ENST00000556285.1	TSL:1	c.755-38T>C	intron	N/A	ENSP00000451110.1	P10600-2
TGFB3	ENST00000964917.1		c.917-38T>C	intron	N/A	ENSP00000634976.1

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20883

AN:

152044

Hom.:

2264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.0397

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0633

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0741

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.0921

AC:

23034

AN:

250042

AF XY:

0.0911

show subpopulations

Gnomad AFR exome

AF:

0.301

Gnomad AMR exome

AF:

0.0686

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.0296

Gnomad FIN exome

AF:

0.0684

Gnomad NFE exome

AF:

0.0763

Gnomad OTH exome

AF:

0.0924

GnomAD4 exome

AF:

0.0839

AC:

122611

AN:

1461052

Hom.:

6336

Cov.:

AF XY:

0.0844

AC XY:

61321

AN XY:

726862

show subpopulations

African (AFR)

AF:

0.308

AC:

10311

AN:

33466

American (AMR)

AF:

0.0726

AC:

3246

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

3026

AN:

26134

East Asian (EAS)

AF:

0.0562

AC:

2232

AN:

39700

South Asian (SAS)

AF:

0.115

AC:

9960

AN:

86240

European-Finnish (FIN)

AF:

0.0699

AC:

3702

AN:

52988

Middle Eastern (MID)

AF:

0.0947

AC:

532

AN:

5620

European-Non Finnish (NFE)

AF:

0.0754

AC:

83823

AN:

1111822

Other (OTH)

AF:

0.0957

AC:

5779

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

6522

13044

19566

26088

32610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3256

6512

9768

13024

16280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.138

AC:

20945

AN:

152162

Hom.:

2283

Cov.:

AF XY:

0.134

AC XY:

9982

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.297

AC:

12324

AN:

41464

American (AMR)

AF:

0.0936

AC:

1433

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

398

AN:

3472

East Asian (EAS)

AF:

0.0398

AC:

206

AN:

5182

South Asian (SAS)

AF:

0.114

AC:

550

AN:

4824

European-Finnish (FIN)

AF:

0.0633

AC:

672

AN:

10610

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0741

AC:

5038

AN:

67992

Other (OTH)

AF:

0.131

AC:

277

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

844

1688

2531

3375

4219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.127

Hom.:

467

Bravo

AF:

0.146

Asia WGS

AF:

0.101

AC:

350

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.8

(source)

DANN

Benign

0.53

PhyloP100

-0.13

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over