rs113194608

Variant names:

• chr3-30672245-C-T
• rs113194608
• NM_003242.6:c.1062C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-30672245-C-T
• chr3-30672245-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003242.6(TGFBR2):​c.1062C>T​(p.Leu354Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,604,244 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (34 hom.)
• Consequence: TGFBR2 NM_003242.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.192
• Publications: 4 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, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-30672245-C-T is Benign according to our data. Variant chr3-30672245-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00238 (362/152328) while in subpopulation SAS AF = 0.0145 (70/4824). AF 95% confidence interval is 0.0118. There are 3 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 362 AD,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.1062C>T	p.Leu354Leu	synonymous	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1245C>T	p.Leu415Leu	synonymous	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1170C>T	p.Leu390Leu	synonymous	Exon 5 of 8	NP_001394056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.1062C>T	p.Leu354Leu	synonymous	Exon 4 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1137C>T	p.Leu379Leu	synonymous	Exon 5 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.1062C>T	p.Leu354Leu	synonymous	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 363 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00376 AC: 922 AN: 245216 AF XY: 0.00470

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00359 AC: 5206 AN: 1451916 Hom.: 34 Cov.: 34 AF XY: 0.00403 AC XY: 2908 AN XY: 720770

African (AFR) AF: 0.000421 AC: 14 AN: 33290

American (AMR) AF: 0.00214 AC: 95 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.0000787 AC: 2 AN: 25398

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39564

South Asian (SAS) AF: 0.0150 AC: 1274 AN: 85010

European-Finnish (FIN) AF: 0.000264 AC: 14 AN: 53038

Middle Eastern (MID) AF: 0.00647 AC: 37 AN: 5718

European-Non Finnish (NFE) AF: 0.00324 AC: 3581 AN: 1105526

Other (OTH) AF: 0.00302 AC: 181 AN: 59952

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74486

African (AFR) AF: 0.000601 AC: 25 AN: 41590

American (AMR) AF: 0.00235 AC: 36 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00298 AC: 203 AN: 68022

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00233

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Loeys-Dietz syndrome 2 (1)
-	-	1	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.2
DANN	Benign	0.79
PhyloP100		0.19
Mutation Taster		=98/2	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: rs113194608; hg19: chr3-30713737;