rs34833812

Variant names:

• chr3-30672127-C-T
• rs34833812
• NM_003242.6:c.944C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-30672127-C-T
• chr3-30672127-C-A
• chr3-30672127-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003242.6(TGFBR2):​c.944C>T​(p.Thr315Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,614,120 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T315T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (9 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:16
• Conservation: PhyloP100: 1.63
• Publications: 30 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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_003242.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 91 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.2437 (below the threshold of 3.09). Trascript score misZ: 2.9378 (below the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome 2, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008349359).
• BP6: Variant 3-30672127-C-T is Benign according to our data. Variant chr3-30672127-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000486 (74/152262) while in subpopulation EAS AF = 0.0135 (70/5180). AF 95% confidence interval is 0.011. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 74 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.944C>T	p.Thr315Met	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1127C>T	p.Thr376Met	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1052C>T	p.Thr351Met	missense	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.944C>T	p.Thr315Met	missense	Exon 4 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1019C>T	p.Thr340Met	missense	Exon 5 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.944C>T	p.Thr315Met	missense	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00112 AC: 280 AN: 251058 AF XY: 0.00108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000395 AC: 578 AN: 1461858 Hom.: 9 Cov.: 34 AF XY: 0.000418 AC XY: 304 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0124 AC: 492 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112000

Other (OTH) AF: 0.000447 AC: 27 AN: 60394

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74442

African (AFR) AF: 0.0000481 AC: 2 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

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: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000501 Hom.: 1

Bravo AF: 0.000733

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	4	not provided (4)
-	-	2	Marfan syndrome (2)
-	-	2	not specified (2)
1	-	-	Colorectal cancer, hereditary nonpolyposis, type 6 (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial colorectal cancer (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.0020
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Benign	0.047	D
Sift4G	Benign	0.11	T
Polyphen		0.44	B
Vest4		0.13
MVP		0.99
MPC		0.63
ClinPred		0.040	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.47
Mutation Taster		=91/9	disease causing (ClinVar)

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: rs34833812; hg19: chr3-30713619;