3-30650235-T-G

Variant names:

• chr3-30650235-T-G
• rs11466495
• NM_003242.6:c.264-35T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003242.6(TGFBR2):​c.264-35T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,598,726 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (27 hom.)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.581
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-30650235-T-G is Benign according to our data. Variant chr3-30650235-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00866 (1317/152136) while in subpopulation AFR AF = 0.0305 (1267/41502). AF 95% confidence interval is 0.0291. There are 17 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1317 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003242.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.264-35T>G		intron	N/A	NP_003233.4
	TGFBR2	NM_001407126.1		c.339-35T>G		intron	N/A	NP_001394055.1
	TGFBR2	NM_001407127.1		c.264-35T>G		intron	N/A	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.264-35T>G		intron	N/A	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.339-35T>G		intron	N/A	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.237-35T>G		intron	N/A	ENSP00000519658.1

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1317 AN: 152018 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

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: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00220 AC: 549 AN: 249764 AF XY: 0.00165

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000924 AC: 1336 AN: 1446590 Hom.: 27 Cov.: 28 AF XY: 0.000798 AC XY: 575 AN XY: 720762

African (AFR) AF: 0.0349 AC: 1157 AN: 33184

American (AMR) AF: 0.00110 AC: 49 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.0000246 AC: 27 AN: 1098184

Other (OTH) AF: 0.00162 AC: 97 AN: 59890

GnomAD4 genome AF: 0.00866 AC: 1317 AN: 152136 Hom.: 17 Cov.: 32 AF XY: 0.00817 AC XY: 608 AN XY: 74394

African (AFR) AF: 0.0305 AC: 1267 AN: 41502

American (AMR) AF: 0.00242 AC: 37 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67992

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00466 Hom.: 2

Bravo AF: 0.0102

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Diabetic retinopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.40
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs11466495; hg19: chr3-30691727;