3-30672127-C-T
Variant names:
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
NM_003242.6 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 1.63
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=0.008349359).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.944C>T | p.Thr315Met | missense_variant | Exon 4 of 7 | 1 | NM_003242.6 | ENSP00000295754.5 | ||
TGFBR2 | ENST00000359013.4 | c.1019C>T | p.Thr340Met | missense_variant | Exon 5 of 8 | 1 | ENSP00000351905.4 | |||
TGFBR2 | ENST00000672866.1 | n.2540C>T | non_coding_transcript_exon_variant | Exon 4 of 7 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152144Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00112 AC: 280AN: 251058Hom.: 3 AF XY: 0.00108 AC XY: 146AN XY: 135674
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GnomAD4 exome AF: 0.000395 AC: 578AN: 1461858Hom.: 9 Cov.: 34 AF XY: 0.000418 AC XY: 304AN XY: 727228
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GnomAD4 genome AF: 0.000486 AC: 74AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74442
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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
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 16, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2018 | This variant is associated with the following publications: (PMID: 17935258, 9590282, 22995991, 20144264, 15235604, 16251899, 18339844, 27647783, 31769227) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | TGFBR2: BP4, BS1, BS2 - |
Marfan syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 27, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2024 | - - |
Colorectal cancer, hereditary nonpolyposis, type 6 Pathogenic:1
Pathogenic, flagged submission | literature only | OMIM | May 01, 1998 | - - |
Familial colorectal cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 10, 2023 | - - |
Loeys-Dietz syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Ehlers-Danlos syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2020 | - - |
Loeys-Dietz syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 10, 2019 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Benign
T
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Benign
D;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
0.63
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at