3-30644922-A-G

Position:

chr3-30644922-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003242.6(TGFBR2):c.263+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,611,264 control chromosomes in the GnomAD database, including 98,950 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9561 hom., cov: 32)

Exomes 𝑓: 0.34 ( 89389 hom. )

Consequence

TGFBR2
NM_003242.6 splice_region, intron

Scores

Splicing: ADA: 0.00002644

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -1.23

Variant links:

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

TGFBR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

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

BP6

Variant 3-30644922-A-G is Benign according to our data. Variant chr3-30644922-A-G is described in ClinVar as [Benign]. Clinvar id is 36867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30644922-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6 linkuse as main transcript	c.263+7A>G		splice_region_variant, intron_variant		ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10 linkuse as main transcript	c.263+7A>G	splice_region_variant, intron_variant	1	NM_003242.6	P1	P37173-1
TGFBR2	ENST00000359013.4 linkuse as main transcript	c.338+7A>G	splice_region_variant, intron_variant	1			P37173-2
TGFBR2	ENST00000672866.1 linkuse as main transcript	n.1859+7A>G	splice_region_variant, intron_variant, non_coding_transcript_variant
TGFBR2	ENST00000673250.1 linkuse as main transcript	n.387+7A>G	splice_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52774

AN:

151882

Hom.:

9569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.255

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.259

Gnomad EAS

AF:

0.687

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.329

GnomAD3 exomes

AF:

0.370

AC:

92790

AN:

250742

Hom.:

18358

AF XY:

0.369

AC XY:

49975

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.694

Gnomad SAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.385

Gnomad NFE exome

AF:

0.341

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.344

AC:

501272

AN:

1459262

Hom.:

89389

Cov.:

AF XY:

0.344

AC XY:

249995

AN XY:

726116

show subpopulations

Gnomad4 AFR exome

AF:

0.336

Gnomad4 AMR exome

AF:

0.341

Gnomad4 ASJ exome

AF:

0.253

Gnomad4 EAS exome

AF:

0.666

Gnomad4 SAS exome

AF:

0.362

Gnomad4 FIN exome

AF:

0.386

Gnomad4 NFE exome

AF:

0.331

Gnomad4 OTH exome

AF:

0.346

GnomAD4 genome

AF:

0.347

AC:

52787

AN:

152002

Hom.:

9561

Cov.:

AF XY:

0.349

AC XY:

25951

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.337

Gnomad4 AMR

AF:

0.304

Gnomad4 ASJ

AF:

0.259

Gnomad4 EAS

AF:

0.686

Gnomad4 SAS

AF:

0.367

Gnomad4 FIN

AF:

0.380

Gnomad4 NFE

AF:

0.337

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.333

Hom.:

13551

Bravo

AF:

0.342

Asia WGS

AF:

0.497

AC:

1731

AN:

3478

EpiCase

AF:

0.322

EpiControl

AF:

0.325

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 56% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 09, 2019	- -

Loeys-Dietz syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Marfan syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 14, 2021

- -

Thoracic aortic aneurysm

Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.054

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0040

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