rs201453600

Variant names:

• chr14-75971659-A-C
• rs201453600
• NM_003239.5:c.412T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 2.83
• Publications: 3 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]

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

ACMG classification

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.

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.412T>G	p.Ser138Ala	missense	Exon 2 of 7	NP_003230.1
	TGFB3	NM_001329939.2		c.412T>G	p.Ser138Ala	missense	Exon 3 of 8	NP_001316868.1
	TGFB3	NM_001329938.2		c.412T>G	p.Ser138Ala	missense	Exon 2 of 5	NP_001316867.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.412T>G	p.Ser138Ala	missense	Exon 2 of 7	ENSP00000238682.3
	TGFB3	ENST00000556285.1	TSL:1	c.412T>G	p.Ser138Ala	missense	Exon 2 of 5	ENSP00000451110.1
	TGFB3	ENST00000964917.1		c.574T>G	p.Ser192Ala	missense	Exon 3 of 8	ENSP00000634976.1

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

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251440 AF XY: 0.0000957

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000201 AC: 223 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	1	1	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not specified (2)
-	2	-	Rienhoff syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.41	N
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.066
Sift	Benign	0.67	T
Sift4G	Benign	0.69	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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

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