Genetic Variant NM_003243.5:c.2293G>C (chr1-91698125-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003243.5(TGFBR3):c.2293G>C(p.Gly765Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,613,652 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 46 hom. )

Consequence

TGFBR3
NM_003243.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0380

Publications

13 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

new If you want to explore the variant's impact on the transcript NM_003243.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028454661).

BP6

Variant 1-91698125-C-G is Benign according to our data. Variant chr1-91698125-C-G is described in ClinVar as Benign. ClinVar VariationId is 777326.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 = 0.00405 (617/152232) while in subpopulation EAS AF = 0.0338 (175/5178). AF 95% confidence interval is 0.0297. There are 6 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 617 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.2293G>C	p.Gly765Arg	missense	Exon 15 of 17	NP_003234.2	Q03167-1
TGFBR3	NM_001195683.2		c.2290G>C	p.Gly764Arg	missense	Exon 15 of 17	NP_001182612.1	A0A0A8KWK3
TGFBR3	NM_001195684.1		c.2290G>C	p.Gly764Arg	missense	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.2293G>C	p.Gly765Arg	missense	Exon 15 of 17	ENSP00000212355.4	Q03167-1
TGFBR3	ENST00000525962.5	TSL:1	c.2293G>C	p.Gly765Arg	missense	Exon 14 of 16	ENSP00000436127.1	Q03167-1
TGFBR3	ENST00000370399.6	TSL:1	c.2290G>C	p.Gly764Arg	missense	Exon 16 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0339

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00711

AC:

1787

AN:

251370

AF XY:

0.00643

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0273

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00397

AC:

5800

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

2826

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33474

American (AMR)

AF:

0.0222

AC:

993

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26130

East Asian (EAS)

AF:

0.0336

AC:

1331

AN:

39666

South Asian (SAS)

AF:

0.00369

AC:

318

AN:

86246

European-Finnish (FIN)

AF:

0.00240

AC:

128

AN:

53410

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00250

AC:

2780

AN:

1111632

Other (OTH)

AF:

0.00346

AC:

209

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

294

588

883

1177

1471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00405

AC:

617

AN:

152232

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

340

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41548

American (AMR)

AF:

0.0138

AC:

211

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5178

South Asian (SAS)

AF:

0.00519

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00216

AC:

147

AN:

68008

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00330

Hom.:

Bravo

AF:

0.00551

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00273

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

TGFBR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.6

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.19

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

0.038

PrimateAI

Benign

0.22

PROVEAN

Benign

0.0

REVEL

Benign

0.061

Sift

Benign

0.56

Sift4G

Benign

0.60

Varity_R

0.037

gMVP

0.37

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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