rs1805110

chr1-91861488-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003243.5(TGFBR3):c.44C>T(p.Ser15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,018 control chromosomes in the GnomAD database, including 11,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.13 (1643 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9995 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004665315).
• BP6: Variant 1-91861488-G-A is Benign according to our data. Variant chr1-91861488-G-A is described in ClinVar as [Benign]. Clinvar id is 3060183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5	c.44C>T	p.Ser15Phe	missense_variant	2/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.44C>T	p.Ser15Phe	missense_variant	2/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19741 AN: 151990 Hom.: 1635 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0936

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0844

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.131 AC: 33006 AN: 251414 Hom.: 3003 AF XY: 0.129 AC XY: 17493 AN XY: 135892

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.397

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0856

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.100 AC: 146296 AN: 1459910 Hom.: 9995 Cov.: 30 AF XY: 0.101 AC XY: 73264 AN XY: 726348

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0809

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.130 AC: 19782 AN: 152108 Hom.: 1643 Cov.: 32 AF XY: 0.132 AC XY: 9792 AN XY: 74360

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0844

Gnomad4 OTH AF: 0.127

Alfa AF: 0.101 Hom.: 2156

Bravo AF: 0.135

TwinsUK AF: 0.0833 AC: 309

ALSPAC AF: 0.0838 AC: 323

ESP6500AA AF: 0.175 AC: 771

ESP6500EA AF: 0.0848 AC: 729

ExAC AF: 0.131 AC: 15872

Asia WGS AF: 0.236 AC: 819 AN: 3478

EpiCase AF: 0.0852

EpiControl AF: 0.0836

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TGFBR3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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	-0.53	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.11	T;.;T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T;.;.;T;T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;.
MutationTaster	Benign	0.57	P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.25	N;N;N;N;D
REVEL	Benign	0.094
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.12
MPC		0.25
ClinPred		0.0078	T
GERP RS		3.2
Varity_R		0.058
gMVP		0.15

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: rs1805110; hg19: chr1-92327045; COSMIC: COSV53023135; COSMIC: COSV53023135;