3-30692346-C-G

Position:

• chr3-30692346-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000295754.10(TGFBR2):​c.*747C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 230,126 control chromosomes in the GnomAD database, including 1,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1232 hom., cov: 32)
  • Exomes 𝑓: 0.057 (182 hom.)
• Consequence: TGFBR2 ENST00000295754.10 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.182

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-30692346-C-G is Benign according to our data. Variant chr3-30692346-C-G is described in ClinVar as [Benign]. Clinvar id is 344681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.*747C>G		3_prime_UTR_variant	7/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.*747C>G		3_prime_UTR_variant	7/7	1	NM_003242.6	ENSP00000295754	P1
TGFBR2	ENST00000359013.4	c.*747C>G		3_prime_UTR_variant	8/8	1		ENSP00000351905
TGFBR2	ENST00000672866.1	n.4047C>G		non_coding_transcript_exon_variant	7/7
TGFBR2	ENST00000673203.1	n.1329C>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15525 AN: 152046 Hom.: 1224 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0845

GnomAD4 exome AF: 0.0571 AC: 4452 AN: 77962 Hom.: 182 Cov.: 0 AF XY: 0.0552 AC XY: 1977 AN XY: 35832

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.0659

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.0855

Gnomad4 FIN exome AF: 0.0795

Gnomad4 NFE exome AF: 0.0474

Gnomad4 OTH exome AF: 0.0782

GnomAD4 genome AF: 0.102 AC: 15564 AN: 152164 Hom.: 1232 Cov.: 32 AF XY: 0.104 AC XY: 7740 AN XY: 74398

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.0950

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.0477

Gnomad4 OTH AF: 0.0836

Alfa AF: 0.0148 Hom.: 5

Bravo AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Marfan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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 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	-0.82
CADD	Benign	1.3
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11466531; hg19: chr3-30733838; COSMIC: COSV55449375;