rs147586574

chr1-91861477-T-Cchr1-91861477-T-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.55A>G(p.Thr19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,611,870 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (33 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.176

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=0.0033077002).
• BP6: Variant 1-91861477-T-C is Benign according to our data. Variant chr1-91861477-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 547813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5	c.55A>G	p.Thr19Ala	missense_variant	2/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.55A>G	p.Thr19Ala	missense_variant	2/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152202 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00404 AC: 1016 AN: 251438 Hom.: 16 AF XY: 0.00395 AC XY: 537 AN XY: 135892

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00306 AC: 4463 AN: 1459550 Hom.: 33 Cov.: 29 AF XY: 0.00297 AC XY: 2155 AN XY: 726298

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0284

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152320 Hom.: 7 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74496

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0288

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00254 Hom.: 3

Bravo AF: 0.00128

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00368 AC: 447

EpiCase AF: 0.00234

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

TGFBR3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as likely 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	0.061
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.7
Dann	Benign	0.25
DEOGEN2	Benign	0.12	T;.;T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T;.;.;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.53	N;N;N;N;D
REVEL	Benign	0.0070
Sift	Benign	0.10	T;T;T;T;D
Sift4G	Benign	0.82	T;T;T;T;.
Polyphen		0.10	B;B;B;B;.
Vest4		0.16
MVP		0.45
MPC		0.22
ClinPred		0.0042	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.21

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: rs147586574; hg19: chr1-92327034; COSMIC: COSV105820764; COSMIC: COSV105820764;