Genetic Variant NM_003243.5:c.216A>G (chr1-91797317-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003243.5(TGFBR3):c.216A>G(p.Ala72Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,988 control chromosomes in the GnomAD database, including 346,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34618 hom., cov: 33)

Exomes 𝑓: 0.65 ( 311737 hom. )

Consequence

TGFBR3
NM_003243.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.30

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-91797317-T-C is Benign according to our data. Variant chr1-91797317-T-C is described in ClinVar as [Benign]. Clinvar id is 1276034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR3	NM_003243.5 link	c.216A>G	p.Ala72Ala	synonymous_variant	Exon 3 of 17	ENST00000212355.9	NP_003234.2	Q03167-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR3	ENST00000212355.9 link	c.216A>G	p.Ala72Ala	synonymous_variant	Exon 3 of 17	1	NM_003243.5	ENSP00000212355.4		Q03167-1

Frequencies

GnomAD3 genomes

AF:

0.672

AC:

102201

AN:

152038

Hom.:

34570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.746

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.660

Gnomad ASJ

AF:

0.611

Gnomad EAS

AF:

0.786

Gnomad SAS

AF:

0.678

Gnomad FIN

AF:

0.597

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.638

Gnomad OTH

AF:

0.658

GnomAD3 exomes

AF:

0.660

AC:

165761

AN:

251248

Hom.:

55338

AF XY:

0.659

AC XY:

89573

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.755

Gnomad AMR exome

AF:

0.643

Gnomad ASJ exome

AF:

0.631

Gnomad EAS exome

AF:

0.782

Gnomad SAS exome

AF:

0.682

Gnomad FIN exome

AF:

0.605

Gnomad NFE exome

AF:

0.639

Gnomad OTH exome

AF:

0.648

GnomAD4 exome

AF:

0.651

AC:

952340

AN:

1461832

Hom.:

311737

Cov.:

AF XY:

0.652

AC XY:

474292

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.754

Gnomad4 AMR exome

AF:

0.645

Gnomad4 ASJ exome

AF:

0.628

Gnomad4 EAS exome

AF:

0.828

Gnomad4 SAS exome

AF:

0.687

Gnomad4 FIN exome

AF:

0.606

Gnomad4 NFE exome

AF:

0.642

Gnomad4 OTH exome

AF:

0.659

GnomAD4 genome

AF:

0.672

AC:

102303

AN:

152156

Hom.:

34618

Cov.:

AF XY:

0.671

AC XY:

49906

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.747

Gnomad4 AMR

AF:

0.660

Gnomad4 ASJ

AF:

0.611

Gnomad4 EAS

AF:

0.786

Gnomad4 SAS

AF:

0.678

Gnomad4 FIN

AF:

0.597

Gnomad4 NFE

AF:

0.638

Gnomad4 OTH

AF:

0.661

Alfa

AF:

0.650

Hom.:

16463

Bravo

AF:

0.681

Asia WGS

AF:

0.709

AC:

2470

AN:

3478

EpiCase

AF:

0.642

EpiControl

AF:

0.638

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

TGFBR3-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.082

DANN

Benign

0.50

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