3-30672302-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_003242.6(TGFBR2):​c.1119G>A​(p.Met373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,608,076 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0017 ( 9 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

4
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:26

Conservation

PhyloP100: 3.11
Variant links:
Genes affected
TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a domain Protein kinase (size 300) in uniprot entity TGFR2_HUMAN there are 34 pathogenic changes around while only 5 benign (87%) in NM_003242.6
BP4
Computational evidence support a benign effect (MetaRNN=0.009409457).
BP6
Variant 3-30672302-G-A is Benign according to our data. Variant chr3-30672302-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672302-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00131 (199/152320) while in subpopulation AMR AF= 0.0034 (52/15310). AF 95% confidence interval is 0.00266. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR2NM_003242.6 linkc.1119G>A p.Met373Ile missense_variant Exon 4 of 7 ENST00000295754.10 NP_003233.4 P37173-1A3QNQ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFBR2ENST00000295754.10 linkc.1119G>A p.Met373Ile missense_variant Exon 4 of 7 1 NM_003242.6 ENSP00000295754.5 P37173-1
TGFBR2ENST00000359013.4 linkc.1194G>A p.Met398Ile missense_variant Exon 5 of 8 1 ENSP00000351905.4 P37173-2
TGFBR2ENST00000672866.1 linkn.2715G>A non_coding_transcript_exon_variant Exon 4 of 7

Frequencies

GnomAD3 genomes
AF:
0.00131
AC:
200
AN:
152202
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000289
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00340
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00169
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00144
AC:
354
AN:
246454
Hom.:
2
AF XY:
0.00134
AC XY:
178
AN XY:
132926
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00373
Gnomad ASJ exome
AF:
0.00351
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000142
Gnomad NFE exome
AF:
0.00139
Gnomad OTH exome
AF:
0.00516
GnomAD4 exome
AF:
0.00175
AC:
2544
AN:
1455756
Hom.:
9
Cov.:
34
AF XY:
0.00171
AC XY:
1237
AN XY:
723518
show subpopulations
Gnomad4 AFR exome
AF:
0.000180
Gnomad4 AMR exome
AF:
0.00391
Gnomad4 ASJ exome
AF:
0.00278
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.000320
Gnomad4 NFE exome
AF:
0.00193
Gnomad4 OTH exome
AF:
0.00223
GnomAD4 genome
AF:
0.00131
AC:
199
AN:
152320
Hom.:
1
Cov.:
33
AF XY:
0.00134
AC XY:
100
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.00340
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.00168
Gnomad4 OTH
AF:
0.00425
Alfa
AF:
0.00152
Hom.:
0
Bravo
AF:
0.00149
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00163
AC:
14
ExAC
AF:
0.00135
AC:
164
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TGFBR2: BS1 -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 24, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17344846, 16928994, 9395234, 23884466, 27153395, 18781618) -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 06, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:6
Mar 16, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 25, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 23, 2019
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. -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

LB/B > 4 on ClinVar or LB/B > 2 Rep -

Jun 15, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has previously been reported in the literature in an individual wit h clinical features of Loeys-Dietz syndrome; however, the variant was also found in 1/200 control chromosomes (Loeys 2006) and in the reportedly unaffected pare nt of a proband in our laboratory. In addition, this residue is not highly conse rved through different species, which raises the possibility that amino acid cha nges at this position may be tolerated. Therefore, this variant is likely to be benign. -

Jan 14, 2019
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 06, 2017
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Loeys-Dietz syndrome Uncertain:1Benign:2
Feb 23, 2015
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 17, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Marfan syndrome Benign:2
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Benign:1
Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TGFBR2 NM_003242.5 exon 4 p.Met373Ile (c.1119G>A): This variant has been reported in the literature in one individual with Loeys-Dietz syndrome (Frischmeyer-Guerrerio 2013 PMID:23884466). However, this variant isalso present in 0.3% (47/13666) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-30672302-G-A?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:36859). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Ehlers-Danlos syndrome Benign:1
May 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Loeys-Dietz syndrome 2 Benign:1
Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Connective tissue disorder Benign:1
Jun 01, 2018
Center for Human Genetics, Inc, Center for Human Genetics, Inc
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
0.23
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
21
DANN
Benign
0.95
DEOGEN2
Benign
0.39
T;.
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.0094
T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
-0.060
N;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
0.34
N;N
REVEL
Benign
0.23
Sift
Benign
0.43
T;T
Sift4G
Benign
0.46
T;T
Polyphen
0.0020
B;.
Vest4
0.11
MutPred
0.31
Loss of glycosylation at P371 (P = 0.0388);.;
MVP
0.94
MPC
0.59
ClinPred
0.015
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21
gMVP
0.33

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.

Other links and lift over

dbSNP: rs35719192; hg19: chr3-30713794; COSMIC: COSV55458038; API