NM_003242.6:c.*835C>A

Variant names:

• chr3-30692434-C-A
• rs17026332
• NM_003242.6:c.*835C>A

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.*835C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 231,860 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (9 hom.)
• Consequence: TGFBR2 NM_003242.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.401
• Publications: 5 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=-0.8).
• BP6: Variant 3-30692434-C-A is Benign according to our data. Variant chr3-30692434-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 344684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00975 (1485/152284) while in subpopulation AMR AF = 0.0152 (232/15300). AF 95% confidence interval is 0.0138. There are 10 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1485 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.*835C>A		3_prime_UTR	Exon 7 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.*835C>A		3_prime_UTR	Exon 9 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.*835C>A		3_prime_UTR	Exon 8 of 8	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.*835C>A		3_prime_UTR	Exon 7 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.*835C>A		3_prime_UTR	Exon 8 of 8	ENSP00000351905.4
	TGFBR2	ENST00000941789.1		c.*835C>A		3_prime_UTR	Exon 7 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1485 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0109 AC: 871 AN: 79576 Hom.: 9 Cov.: 0 AF XY: 0.0107 AC XY: 392 AN XY: 36606

African (AFR) AF: 0.00422 AC: 16 AN: 3794

American (AMR) AF: 0.0126 AC: 31 AN: 2452

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 12 AN: 5046

East Asian (EAS) AF: 0.000265 AC: 3 AN: 11332

South Asian (SAS) AF: 0.00 AC: 0 AN: 688

European-Finnish (FIN) AF: 0.0185 AC: 1 AN: 54

Middle Eastern (MID) AF: 0.0102 AC: 5 AN: 488

European-Non Finnish (NFE) AF: 0.0149 AC: 732 AN: 49084

Other (OTH) AF: 0.0107 AC: 71 AN: 6638

GnomAD4 genome AF: 0.00975 AC: 1485 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74468

African (AFR) AF: 0.00262 AC: 109 AN: 41572

American (AMR) AF: 0.0152 AC: 232 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0145 AC: 987 AN: 68002

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

Alfa AF: 0.0119 Hom.: 4

Bravo AF: 0.0103

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.6
DANN	Benign	0.68
PhyloP100		0.40
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: rs17026332; hg19: chr3-30733926;