3-30691329-C-A

Variant names:

• chr3-30691329-C-A
• rs2276767
• NM_003242.6:c.1525-91C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003242.6(TGFBR2):​c.1525-91C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,427,188 control chromosomes in the GnomAD database, including 64,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4746 hom., cov: 32)
  • Exomes 𝑓: 0.29 (59394 hom.)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0520
• Publications: 17 publications found

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]

TGFBR2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-30691329-C-A is Benign according to our data. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-30691329-C-A is described in CliVar as Benign. Clinvar id is 2687926.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1525-91C>A		intron_variant	Intron 6 of 6	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1525-91C>A		intron_variant	Intron 6 of 6	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34320 AN: 152050 Hom.: 4750 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0948

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.294 AC: 375051 AN: 1275020 Hom.: 59394 AF XY: 0.290 AC XY: 185112 AN XY: 637688

African (AFR) AF: 0.0880 AC: 2610 AN: 29668

American (AMR) AF: 0.117 AC: 4335 AN: 37186

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4117 AN: 24540

East Asian (EAS) AF: 0.0870 AC: 3174 AN: 36486

South Asian (SAS) AF: 0.170 AC: 13358 AN: 78532

European-Finnish (FIN) AF: 0.396 AC: 18937 AN: 47858

Middle Eastern (MID) AF: 0.176 AC: 837 AN: 4768

European-Non Finnish (NFE) AF: 0.326 AC: 313704 AN: 962050

Other (OTH) AF: 0.259 AC: 13979 AN: 53932

GnomAD4 genome AF: 0.225 AC: 34303 AN: 152168 Hom.: 4746 Cov.: 32 AF XY: 0.226 AC XY: 16828 AN XY: 74390

African (AFR) AF: 0.0934 AC: 3880 AN: 41558

American (AMR) AF: 0.150 AC: 2300 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3470

East Asian (EAS) AF: 0.0944 AC: 488 AN: 5170

South Asian (SAS) AF: 0.169 AC: 815 AN: 4828

European-Finnish (FIN) AF: 0.394 AC: 4165 AN: 10570

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21409 AN: 67964

Other (OTH) AF: 0.209 AC: 442 AN: 2110

Alfa AF: 0.265 Hom.: 7302

Bravo AF: 0.202

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.61
PhyloP100		0.052
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276767; hg19: chr3-30732821; COSMIC: COSV55443740;