1-91698125-C-G

Position:

chr1-91698125-C-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 617 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR3	NM_003243.5 linkuse as main transcript	c.2293G>C	p.Gly765Arg	missense_variant	15/17	ENST00000212355.9	NP_003234.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR3	ENST00000212355.9 linkuse as main transcript	c.2293G>C	p.Gly765Arg	missense_variant	15/17	1	NM_003243.5	ENSP00000212355	P3	Q03167-1

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

GnomAD3 exomes

AF:

0.00711

AC:

1787

AN:

251370

Hom.:

AF XY:

0.00643

AC XY:

873

AN XY:

135860

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 SAS exome

AF:

0.00330

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

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0336

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.00240

Gnomad4 NFE exome

AF:

0.00250

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00405

AC:

617

AN:

152232

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

340

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.0138

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0338

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00330

Hom.:

Bravo

AF:

0.00551

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00659

AC:

800

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

TGFBR3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.6

DANN

Benign

0.54

DEOGEN2

Benign

0.19

T;.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.54

T;.;.;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

0.0

N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.56

T;T;T;T

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.53

P;P;P;P

Vest4

0.030

MVP

0.42

MPC

0.37

ClinPred

0.0037

GERP RS

2.1

Varity_R

0.037

gMVP

0.37

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over