3-30672127-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003242.6(TGFBR2):c.944C>T(p.Thr315Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,614,120 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T315T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 9 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.63

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]

TGFBR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_003242.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 91 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.2437 (below the threshold of 3.09). Trascript score misZ: 2.9378 (below the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome 2, Rienhoff syndrome, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.008349359).

BP6

Variant 3-30672127-C-T is Benign according to our data. Variant chr3-30672127-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 12502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672127-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000486 (74/152262) while in subpopulation EAS AF = 0.0135 (70/5180). AF 95% confidence interval is 0.011. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.944C>T	p.Thr315Met	missense_variant	Exon 4 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFBR2	ENST00000295754.10 link	c.944C>T	p.Thr315Met	missense_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4 link	c.1019C>T	p.Thr340Met	missense_variant	Exon 5 of 8	1		ENSP00000351905.4	P37173-2
TGFBR2	ENST00000672866.1 link	n.2540C>T		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00112

AC:

280

AN:

251058

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000395

AC:

578

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.0000447

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0124

AC:

492

AN:

39700

Gnomad4 SAS exome

AF:

0.000243

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53398

Gnomad4 NFE exome

AF:

0.0000315

AC:

AN:

1112000

Gnomad4 Remaining exome

AF:

0.000447

AC:

AN:

60394

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

AC:

0.0000481371

AN:

0.0000481371

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000653509

AN:

0.0000653509

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.0135

AC:

0.0135135

AN:

0.0135135

Gnomad4 SAS

AF:

0.000207

AC:

0.000207383

AN:

0.000207383

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.000733

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00102

AC:

124

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Sep 25, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Mar 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17935258, 9590282, 22995991, 20144264, 15235604, 16251899, 18339844, 27647783, 31769227) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGFBR2: BP4, BS1, BS2 -

Marfan syndrome

Benign:2

Aug 22, 2023

Mendelics

Significance: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

- -

not specified

Benign:2

Oct 27, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 6

Pathogenic:1

May 01, 1998

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

Familial colorectal cancer

Benign:1

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome 2

Benign:1

Jan 10, 2019

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Benign

-0.0020

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0083

T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.047

D;T

Sift4G

Benign

0.11

T;T

Polyphen

0.44

B;.

Vest4

0.13

MVP

0.99

MPC

0.63

ClinPred

0.040

GERP RS

3.9

Varity_R

0.13

gMVP

0.47

Mutation Taster

=91/9

disease causing (ClinVar)

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