chr3-30606577-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The XM_047449400.1(LOC105377015):​c.348G>A​(p.Ala116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 319,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

LOC105377015
XM_047449400.1 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.38
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 Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP7
Synonymous conserved (PhyloP=3.38 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LOC105377015XM_047449400.1 linkuse as main transcriptc.348G>A p.Ala116= synonymous_variant 1/2 XP_047305356.1
TGFBR2NM_003242.6 linkuse as main transcript upstream_gene_variant ENST00000295754.10 NP_003233.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGFBR2ENST00000295754.10 linkuse as main transcript upstream_gene_variant 1 NM_003242.6 ENSP00000295754 P1P37173-1
TGFBR2ENST00000359013.4 linkuse as main transcript upstream_gene_variant 1 ENSP00000351905 P37173-2

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000149
AC:
25
AN:
167376
Hom.:
0
Cov.:
0
AF XY:
0.000121
AC XY:
10
AN XY:
82804
show subpopulations
Gnomad4 AFR exome
AF:
0.000174
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000218
Gnomad4 OTH exome
AF:
0.0000866
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000347
Hom.:
0
Bravo
AF:
0.000110

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 19, 2017- -
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 24, 2021- -
Loeys-Dietz syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Diabetic retinopathy Benign:1
Likely benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs749340193 with diabetic retinopathy. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
CADD
Benign
19
DANN
Benign
0.89
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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: rs749340193; hg19: chr3-30648069; COSMIC: COSV55450170; COSMIC: COSV55450170; API