14-75971659-A-C

Position:

• chr14-75971659-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000238682.8(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. 15/21 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 ENST00000238682.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Benign. Variant got -11 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 id is 239520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB3	NM_003239.5	c.412T>G	p.Ser138Ala	missense_variant	2/7	ENST00000238682.8	NP_003230.1
TGFB3	NM_001329939.2	c.412T>G	p.Ser138Ala	missense_variant	3/8		NP_001316868.1
TGFB3	NM_001329938.2	c.412T>G	p.Ser138Ala	missense_variant	2/5		NP_001316867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB3	ENST00000238682.8	c.412T>G	p.Ser138Ala	missense_variant	2/7	1	NM_003239.5	ENSP00000238682	P1
TGFB3	ENST00000556285.1	c.412T>G	p.Ser138Ala	missense_variant	2/5	1		ENSP00000451110
TGFB3	ENST00000556674.2	c.412T>G	p.Ser138Ala	missense_variant	3/8	3		ENSP00000502685	P1
IFT43	ENST00000555677.5	n.90-17226A>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152240 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251440 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135894

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 SAS exome AF: 0.0000327

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.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TGFB3: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2023	See Variant Classification Assertion Criteria. -

Rienhoff syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2024	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:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 11, 2019

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 0.00012 in 277200 control chromosomes, predominantly at a frequency of 0.00025 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 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.412T>G has been reported in the literature in an affected individual (Overwater_2018). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. A co-occurrence with another pathogenic variant has been reported (KCNH2 c.211G>C, p.Gly71Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.41	N;N
MutationTaster	Benign	0.80	D;D
PrimateAI	Uncertain	0.55	T
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	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs201453600; hg19: chr14-76438002; COSMIC: COSV53171483; COSMIC: COSV53171483;