chr3-30606756-C-G

Position:

• chr3-30606756-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The XM_047449400.1(LOC105377015):​c.169G>C​(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 639,490 control chromosomes in the GnomAD database, including 3,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2248 hom., cov: 32)
  • Exomes 𝑓: 0.031 (845 hom.)
• Consequence: LOC105377015 XM_047449400.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.146

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 3-30606756-C-G is Benign according to our data. Variant chr3-30606756-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 344653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC105377015	XM_047449400.1	c.169G>C	p.Gly57Arg	missense_variant	1/2		XP_047305356.1
TGFBR2	NM_003242.6	c.-128C>G		5_prime_UTR_variant	1/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.-128C>G		5_prime_UTR_variant	1/7	1	NM_003242.6	ENSP00000295754	P1
TGFBR2	ENST00000359013.4	c.-128C>G		5_prime_UTR_variant	1/8	1		ENSP00000351905

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16839 AN: 152030 Hom.: 2238 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0853

GnomAD4 exome AF: 0.0313 AC: 15267 AN: 487352 Hom.: 845 Cov.: 7 AF XY: 0.0302 AC XY: 7241 AN XY: 239754

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.0292

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.0206

Gnomad4 NFE exome AF: 0.0209

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.111 AC: 16880 AN: 152138 Hom.: 2248 Cov.: 32 AF XY: 0.111 AC XY: 8241 AN XY: 74388

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.0904

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.0319

Gnomad4 SAS AF: 0.0586

Gnomad4 FIN AF: 0.0243

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0835

Alfa AF: 0.0114 Hom.: 8

Bravo AF: 0.125

Asia WGS AF: 0.0740 AC: 257 AN: 3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Diabetic retinopathy Benign:1

Likely benign, 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 rs2306856 with diabetic retinopathy. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.90

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: rs2306856; hg19: chr3-30648248;