1-91698089-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003243.5(TGFBR3):c.2329C>T(p.Pro777Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0102 in 1,613,536 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: TGFBR3 NM_003243.5 missense, splice_region
• Scores: Splicing: ADA: 0.08694
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.47

Genes affected

TGFBR3 (HGNC:11774): (transforming growth factor beta receptor 3) This locus encodes the transforming growth factor (TGF)-beta type III receptor. The encoded receptor is a membrane proteoglycan that often functions as a co-receptor with other TGF-beta receptor superfamily members. Ectodomain shedding produces soluble TGFBR3, which may inhibit TGFB signaling. Decreased expression of this receptor has been observed in various cancers. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006033629).
• BP6: Variant 1-91698089-G-A is Benign according to our data. Variant chr1-91698089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 547818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 1042 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5	c.2329C>T	p.Pro777Ser	missense_variant, splice_region_variant	15/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.2329C>T	p.Pro777Ser	missense_variant, splice_region_variant	15/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00667 AC: 1677 AN: 251420 Hom.: 6 AF XY: 0.00653 AC XY: 888 AN XY: 135888

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.0105 AC: 15347 AN: 1461252 Hom.: 104 Cov.: 30 AF XY: 0.0103 AC XY: 7489 AN XY: 726974

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.00977

GnomAD4 genome AF: 0.00684 AC: 1042 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00631 AC XY: 470 AN XY: 74466

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.0101 Hom.: 18

Bravo AF: 0.00699

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00663 AC: 805

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

TGFBR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

TGFBR3: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T;.;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.63	T;.;.;T
MetaRNN	Benign	0.0060	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.;N;.
MutationTaster	Benign	0.88	D;D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.72
MVP		0.55
MPC		0.23
ClinPred		0.010	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.086
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.087
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2228363; hg19: chr1-92163646; COSMIC: COSV99059584;