3-30672127-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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 (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00040 ( 9 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

1
5
12

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]

Genome browser will be placed here

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=0.008349359).
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR2NM_003242.6 linkc.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 Appris UniProt
TGFBR2ENST00000295754.10 linkc.944C>T p.Thr315Met missense_variant Exon 4 of 7 1 NM_003242.6 ENSP00000295754.5 P37173-1
TGFBR2ENST00000359013.4 linkc.1019C>T p.Thr340Met missense_variant Exon 5 of 8 1 ENSP00000351905.4 P37173-2
TGFBR2ENST00000672866.1 linkn.2540C>T non_coding_transcript_exon_variant Exon 4 of 7

Frequencies

GnomAD3 genomes
AF:
0.000493
AC:
75
AN:
152144
Hom.:
0
Cov.:
33
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
GnomAD3 exomes
AF:
0.00112
AC:
280
AN:
251058
Hom.:
3
AF XY:
0.00108
AC XY:
146
AN XY:
135674
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 SAS exome
AF:
0.000229
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.:
9
Cov.:
34
AF XY:
0.000418
AC XY:
304
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0124
Gnomad4 SAS exome
AF:
0.000243
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.000447
GnomAD4 genome
AF:
0.000486
AC:
74
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.000497
AC XY:
37
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0135
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000804
Hom.:
1
Bravo
AF:
0.000733
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00102
AC:
124
Asia WGS
AF:
0.00433
AC:
15
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
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

- -

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

- -

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

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
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) -

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
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.
Eigen
Benign
-0.0020
Eigen_PC
Benign
0.12
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.89
D;D
MetaRNN
Benign
0.0083
T;T
MetaSVM
Uncertain
0.34
D
MutationAssessor
Benign
1.6
L;.
PrimateAI
Benign
0.44
T
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
T
GERP RS
3.9
Varity_R
0.13
gMVP
0.47

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: rs34833812; hg19: chr3-30713619; API