chr14-75971659-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_003239.5(TGFB3):c.412T>G(p.Ser138Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TGFB3
NM_003239.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 2.83

Publications

3 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 links:

TGFB3-AS1 (HGNC:53144): (TGFB3 antisense RNA 1)

TGFB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1256491).

BP6

Variant 14-75971659-A-C is Benign according to our data. Variant chr14-75971659-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239520.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000164 (25/152240) while in subpopulation NFE AF = 0.000309 (21/68040). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB3	NM_003239.5 link	c.412T>G	p.Ser138Ala	missense_variant	Exon 2 of 7	ENST00000238682.8	NP_003230.1	P10600-1A5YM40B3KVH9
TGFB3	NM_001329939.2 link	c.412T>G	p.Ser138Ala	missense_variant	Exon 3 of 8		NP_001316868.1	P10600-1A5YM40
TGFB3	NM_001329938.2 link	c.412T>G	p.Ser138Ala	missense_variant	Exon 2 of 5		NP_001316867.1	P10600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8 link	c.412T>G	p.Ser138Ala	missense_variant	Exon 2 of 7	1	NM_003239.5	ENSP00000238682.3		P10600-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000111

AC:

AN:

251440

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

228

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000201

AC:

223

AN:

1112012

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000164

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68040

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000289

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGFB3: BP4 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 03, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TGFB3 c.412T>G; p.Ser138Ala variant (rs201453600; ClinVar Variation ID: 239520) is reported in the literature in an individual affected with a suspected heritable thoracic aortic disorder, although its clinical significance was not certain (Overwater 2018). This variant was also reported in an individual with arrhythmogenic cardiomyopathy but was also identified in a healthy control (Goudal 2022). This variant is observed in the non-Finnish European population with an overall allele frequency of 0.02% (32/129150 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.066). However, due to limited information, the clinical significance of the p.Ser138Ala variant is uncertain at this time. References: Goudal A et al. Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management. Hum Mutat. 2022 Sep;43(9):1333-1342. PMID: 35819174. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Rienhoff syndrome

Uncertain:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 138 of the TGFB3 protein (p.Ser138Ala). This variant is present in population databases (rs201453600, gnomAD 0.03%). This missense change has been observed in individual(s) with TGFB3-related disease (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 239520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TGFB3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:1

Jan 17, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:2

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TGFB3 c.412T>G (p.Ser138Ala) results in a conservative amino acid change located in the TGF-beta, propeptide domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251440 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Arrhythmia phenotype (1e-05). c.412T>G has been observed in individual(s) affected with Arrhythmia. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 239520). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

0.015

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.41

N;N

PhyloP100

2.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.066

Sift

Benign

0.67

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0040

B;.

Vest4

0.31

MVP

0.60

MPC

0.50

ClinPred

0.10

GERP RS

5.7

Varity_R

0.11

gMVP

0.24

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over