rs17882828

Positions:

• chr1-91698125-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0380

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 -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	UniProt
TGFBR3	NM_003243.5	c.2293G>C	p.Gly765Arg	missense_variant	15/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.2293G>C	p.Gly765Arg	missense_variant	15/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152114 Hom.: 5 Cov.: 32

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.: 14 AF XY: 0.00643 AC XY: 873 AN XY: 135860

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.: 46 Cov.: 30 AF XY: 0.00389 AC XY: 2826 AN XY: 727020

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.: 6 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74418

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.: 3

Bravo AF: 0.00551

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00659 AC: 800

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	T
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	N
LIST_S2	Benign	0.54	T;.;.;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs17882828; hg19: chr1-92163682; COSMIC: COSV53025772;