chr1-91698089-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 15/23 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:4

Conservation

PhyloP100: 4.47

Publications

15 publications found

Variant links:

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]

TGFBR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 547818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1042 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003243.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR3	NM_003243.5	MANE Select	c.2329C>T	p.Pro777Ser	missense splice_region	Exon 15 of 17	NP_003234.2	Q03167-1
TGFBR3	NM_001195683.2		c.2326C>T	p.Pro776Ser	missense splice_region	Exon 15 of 17	NP_001182612.1	A0A0A8KWK3
TGFBR3	NM_001195684.1		c.2326C>T	p.Pro776Ser	missense splice_region	Exon 16 of 18	NP_001182613.1	A0A0A8KWK3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR3	ENST00000212355.9	TSL:1 MANE Select	c.2329C>T	p.Pro777Ser	missense splice_region	Exon 15 of 17	ENSP00000212355.4	Q03167-1
TGFBR3	ENST00000525962.5	TSL:1	c.2329C>T	p.Pro777Ser	missense splice_region	Exon 14 of 16	ENSP00000436127.1	Q03167-1
TGFBR3	ENST00000370399.6	TSL:1	c.2326C>T	p.Pro776Ser	missense splice_region	Exon 16 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes

AF:

0.00685

AC:

1042

AN:

152166

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00667

AC:

1677

AN:

251420

AF XY:

0.00653

show subpopulations

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 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.:

AF XY:

0.0103

AC XY:

7489

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33460

American (AMR)

AF:

0.00351

AC:

157

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.00189

AC:

163

AN:

86242

European-Finnish (FIN)

AF:

0.00485

AC:

259

AN:

53414

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

14058

AN:

1111464

Other (OTH)

AF:

0.00977

AC:

590

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

724

1448

2173

2897

3621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00684

AC:

1042

AN:

152284

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

470

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41560

American (AMR)

AF:

0.00510

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00396

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0118

AC:

804

AN:

68020

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00967

Hom.:

Bravo

AF:

0.00699

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00663

AC:

805

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00913

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

TGFBR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

-0.20

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

4.5

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.39

REVEL

Benign

0.065

Sift

Benign

0.45

Sift4G

Benign

0.58

Polyphen

0.0030

Vest4

0.72

MVP

0.55

MPC

0.23

ClinPred

0.010

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.086

gMVP

0.39

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.087

dbscSNV1_RF

Benign

0.21

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over