NM_003242.6:c.95-11985C>T

Variant names:

• chr3-30632762-C-T
• rs12490899
• NM_003242.6:c.95-11985C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003242.6(TGFBR2):​c.95-11985C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 152,164 control chromosomes in the GnomAD database, including 472 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 0.060 (472 hom., cov: 32)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 12 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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.95-11985C>T		intron	N/A	NP_003233.4
	TGFBR2	NM_001407133.1		c.-96C>T		5_prime_UTR	Exon 3 of 9	NP_001394062.1
	TGFBR2	NM_001407135.1		c.-96C>T		5_prime_UTR	Exon 2 of 8	NP_001394064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.95-11985C>T		intron	N/A	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.169+9489C>T		intron	N/A	ENSP00000351905.4
	TGFBR2	ENST00000672866.1		n.1606C>T		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9151 AN: 152046 Hom.: 476 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0575

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0601 AC: 9143 AN: 152164 Hom.: 472 Cov.: 32 AF XY: 0.0654 AC XY: 4864 AN XY: 74408

African (AFR) AF: 0.0444 AC: 1845 AN: 41508

American (AMR) AF: 0.0804 AC: 1229 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1406 AN: 5162

South Asian (SAS) AF: 0.143 AC: 691 AN: 4824

European-Finnish (FIN) AF: 0.0763 AC: 808 AN: 10596

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2844 AN: 68008

Other (OTH) AF: 0.0583 AC: 123 AN: 2108

Alfa AF: 0.0464 Hom.: 396

Bravo AF: 0.0583

Asia WGS AF: 0.222 AC: 770 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		0.28
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: rs12490899; hg19: chr3-30674254;