3-30606582-A-G

Variant names:

• chr3-30606582-A-G
• rs138010137
• XM_047449400.1:c.343T>C

Variant summary

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

The NM_001407129.1(TGFBR2):​c.-23A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 324,702 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: TGFBR2 NM_001407129.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.02
• Publications: 3 publications found

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]

TGFBR2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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=-0.59).
• BP6: Variant 3-30606582-A-G is Benign according to our data. Variant chr3-30606582-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 344649.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 = 0.00758 (1153/152180) while in subpopulation AFR AF = 0.0259 (1075/41526). AF 95% confidence interval is 0.0246. There are 17 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1153 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407129.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_001407129.1		c.-23A>G		5_prime_UTR	Exon 1 of 8	NP_001394058.1
	TGFBR2	NM_001407132.1		c.-23A>G		5_prime_UTR	Exon 1 of 7	NP_001394061.1	A0AAQ5BI06
	TGFBR2	NM_003242.6	MANE Select	c.-302A>G		upstream_gene	N/A	NP_003233.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000714391.1		c.-20A>G		5_prime_UTR	Exon 1 of 8	ENSP00000519658.1	A0AAQ5BI03
	TGFBR2	ENST00000714389.1		c.-18A>G		5_prime_UTR	Exon 1 of 7	ENSP00000519656.1	A0AAQ5BI06
	TGFBR2	ENST00000714390.1		c.-23A>G		5_prime_UTR	Exon 1 of 7	ENSP00000519657.1	A0AAQ5BI06

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1149 AN: 152062 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

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: 0.0000441

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00130 AC: 224 AN: 172522 Hom.: 0 Cov.: 0 AF XY: 0.00123 AC XY: 105 AN XY: 85646

African (AFR) AF: 0.0260 AC: 151 AN: 5800

American (AMR) AF: 0.00305 AC: 15 AN: 4924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7374

East Asian (EAS) AF: 0.00 AC: 0 AN: 18140

South Asian (SAS) AF: 0.000639 AC: 1 AN: 1564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13060

Middle Eastern (MID) AF: 0.00108 AC: 1 AN: 930

European-Non Finnish (NFE) AF: 0.0000826 AC: 9 AN: 108904

Other (OTH) AF: 0.00397 AC: 47 AN: 11826

GnomAD4 genome AF: 0.00758 AC: 1153 AN: 152180 Hom.: 17 Cov.: 32 AF XY: 0.00700 AC XY: 521 AN XY: 74390

African (AFR) AF: 0.0259 AC: 1075 AN: 41526

American (AMR) AF: 0.00386 AC: 59 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00506 Hom.: 0

Bravo AF: 0.00867

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Diabetic retinopathy (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Marfan syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.75
PhyloP100		2.0
PromoterAI		-0.034	Neutral
Mutation Taster		=300/0	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: rs138010137; hg19: chr3-30648074;