rs138514914

chr1-218405179-G-Achr1-218405179-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003238.6(TGFB2):c.357G>A(p.Pro119=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,582,866 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: TGFB2 NM_003238.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0260

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) 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. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-218405179-G-A is Benign according to our data. Variant chr1-218405179-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 213836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000546 (83/151960) while in subpopulation SAS AF= 0.00104 (5/4824). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.357G>A	p.Pro119=	synonymous_variant	2/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.441G>A	p.Pro147=	synonymous_variant	3/8
TGFB2	NR_138148.2	n.1723G>A		non_coding_transcript_exon_variant	2/7
TGFB2	NR_138149.2	n.1807G>A		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.357G>A	p.Pro119=	synonymous_variant	2/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.441G>A	p.Pro147=	synonymous_variant	3/8	1
TGFB2	ENST00000488793.1	n.21G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000945 AC: 226 AN: 239280 Hom.: 1 AF XY: 0.00102 AC XY: 132 AN XY: 129330

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000539 AC: 771 AN: 1430906 Hom.: 7 Cov.: 30 AF XY: 0.000620 AC XY: 438 AN XY: 706956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0000568

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.000546 AC: 83 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74194

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.000574

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2015

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. -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 08, 2021

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138514914; hg19: chr1-218578521; COSMIC: COSV100860490;