rs10482721

Positions:

chr1-218346973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003238.6(TGFB2):c.272G>A(p.Arg91His) variant causes a missense change. The variant allele was found at a frequency of 0.00382 in 1,613,634 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 18 hom. )

Consequence

TGFB2
NM_003238.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 5.85

Variant links:

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]

TGFB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00862962).

BP6

Variant 1-218346973-G-A is Benign according to our data. Variant chr1-218346973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 213835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218346973-G-A is described in Lovd as [Benign]. Variant chr1-218346973-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00302 (460/152350) while in subpopulation NFE AF= 0.00485 (330/68030). AF 95% confidence interval is 0.00442. There are 4 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6 link	c.272G>A	p.Arg91His	missense_variant	1/7	ENST00000366930.9	NP_003229.1	P61812-1Q59EG9
TGFB2	NM_001135599.4 link	c.272G>A	p.Arg91His	missense_variant	1/8		NP_001129071.1	P61812-2Q59EG9
TGFB2	NR_138148.2 link	n.1638G>A		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2 link	n.1638G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9 link	c.272G>A	p.Arg91His	missense_variant	1/7	1	NM_003238.6	ENSP00000355897.4		P61812-1
TGFB2	ENST00000366929.4 link	c.272G>A	p.Arg91His	missense_variant	1/8	1		ENSP00000355896.4		P61812-2

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00396

AC:

981

AN:

247908

Hom.:

AF XY:

0.00420

AC XY:

565

AN XY:

134508

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.00231

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00370

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00599

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00390

AC:

5700

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

2811

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00419

Gnomad4 FIN exome

AF:

0.000938

Gnomad4 NFE exome

AF:

0.00427

Gnomad4 OTH exome

AF:

0.00419

GnomAD4 genome

AF:

0.00302

AC:

460

AN:

152350

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00485

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00416

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00501

AC:

ExAC

AF:

0.00437

AC:

530

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 03, 2020	- -

Loeys-Dietz syndrome 4

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TGFB2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	Variant summary: The TGFB2 c.272G>A (p.Arg91His) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict damaging outcome for this variant, however in silico predictions are not definitive. This variant was found in 519/98396 control chromosomes (4 homozygotes) from ExAC at a frequency of 0.0052746, which is approximately 422 times the estimated maximal expected allele frequency of a pathogenic TGFB2 variant (0.0000125), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign/likely benign. To our knowledge, the variant of interest has not been reported in affected individuals in literature. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 11, 2018	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. -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics, Erasmus University Medical Center

Nov 18, 2016

- -

Holt-Oram syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.20

Sift

Benign

0.099

T;D

Sift4G

Benign

0.15

T;T

Polyphen

0.98

D;D

Vest4

0.38

MVP

0.82

MPC

1.9

ClinPred

0.017

GERP RS

5.5

Varity_R

0.18

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over