rs727504344

chr3-30606876-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The XM_047449400.1(LOC105377015):c.49C>T(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LOC105377015 XM_047449400.1 missense
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:1 O:1
• Conservation: PhyloP100: 1.65

Genes affected

LOC105377015 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC105377015	XM_047449400.1	c.49C>T	p.Pro17Ser	missense_variant	1/2
TGFBR2	NM_003242.6	c.-8G>A		5_prime_UTR_variant	1/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.-8G>A		5_prime_UTR_variant	1/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.-8G>A		5_prime_UTR_variant	1/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1352528 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 664792

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2012

Variant classified as Uncertain Significance - Favor Benign. The -8G>A variant ( TFGBR2) has not been reported in the literature but has been identified in one i ndividual with clinical features of Marfan syndrome (this individual's son). Th is variant is located in the 5' UTR 8 nucleotides upstream of the translation in itiation codon (ATG). Regulatory variation in the 5' and 3' UTR's could negative ly gene expression through reduced mRNA translation but this type of disease mec hanism has not been reported in Marfan or Loeys-Dietz syndromes. Although this data supports that the -8G>A variant may be benign, additional studies are neede d to fully assess its clinical significance. The clinical significance of this v ariant should be interpreted in the context of this individual's clinical manife station. -

Diabetic retinopathy Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical 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 rs727504344 with diabetic retinopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Uncertain	0.98
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

Other links and lift over

dbSNP: rs727504344; hg19: chr3-30648368;