NM_003242.6:c.455-111A>G

Variant names:

• chr3-30671527-A-G
• rs17026161
• NM_003242.6:c.455-111A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003242.6(TGFBR2):​c.455-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,124,162 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000985 (150/152338) while in subpopulation NFE AF = 0.0015 (102/68036). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 150 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.455-111A>G		intron	N/A	NP_003233.4
	TGFBR2	NM_001407126.1		c.638-111A>G		intron	N/A	NP_001394055.1
	TGFBR2	NM_001407127.1		c.563-111A>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.455-111A>G		intron	N/A	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.530-111A>G		intron	N/A	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.428-111A>G		intron	N/A	ENSP00000519658.1

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00115 AC: 1117 AN: 971824 Hom.: 3 AF XY: 0.00120 AC XY: 598 AN XY: 498700

African (AFR) AF: 0.000207 AC: 5 AN: 24118

American (AMR) AF: 0.00125 AC: 46 AN: 36702

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 25 AN: 21772

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36702

South Asian (SAS) AF: 0.00159 AC: 115 AN: 72142

European-Finnish (FIN) AF: 0.000347 AC: 16 AN: 46140

Middle Eastern (MID) AF: 0.00292 AC: 11 AN: 3762

European-Non Finnish (NFE) AF: 0.00124 AC: 852 AN: 686390

Other (OTH) AF: 0.00104 AC: 46 AN: 44096

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74494

African (AFR) AF: 0.000241 AC: 10 AN: 41572

American (AMR) AF: 0.00118 AC: 18 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.9
DANN	Benign	0.65
PhyloP100		0.42
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: rs17026161; hg19: chr3-30713019;