rs149079126

chr1-91722095-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003243.5(TGFBR3):c.935T>C(p.Met312Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000537 in 1,613,900 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.12

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069850683).
• BP6: Variant 1-91722095-A-G is Benign according to our data. Variant chr1-91722095-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 561334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5	c.935T>C	p.Met312Thr	missense_variant	8/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.935T>C	p.Met312Thr	missense_variant	8/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000781 AC: 196 AN: 251008 Hom.: 1 AF XY: 0.000804 AC XY: 109 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000533 AC: 779 AN: 1461616 Hom.: 4 Cov.: 31 AF XY: 0.000571 AC XY: 415 AN XY: 727094

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74468

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.000638

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000437

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2018

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	19
Dann	Benign	0.83
DEOGEN2	Benign	0.18	T;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	T;.;.;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	0.82	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.090	N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.020	B;B;B;B
Vest4		0.29
MVP		0.53
MPC		0.26
ClinPred		0.039	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.49

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: rs149079126; hg19: chr1-92187652;