NM_003242.6:c.263+7A>G

Variant names:

• chr3-30644922-A-G
• rs1155705
• NM_003242.6:c.263+7A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:18
• Conservation: PhyloP100: -1.23

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]

ACMG classification

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 rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.263+7A>G		splice_region_variant, intron_variant	Intron 2 of 6	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.263+7A>G		splice_region_variant, intron_variant	Intron 2 of 6	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.338+7A>G		splice_region_variant, intron_variant	Intron 3 of 7	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.1859+7A>G		splice_region_variant, intron_variant	Intron 2 of 6
TGFBR2	ENST00000673250.1	n.387+7A>G		splice_region_variant, intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52774 AN: 151882 Hom.: 9569 Cov.: 32

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

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.: 33 AF XY: 0.344 AC XY: 249995 AN XY: 726116

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.: 32 AF XY: 0.349 AC XY: 25951 AN XY: 74274

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:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

May 09, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 2 Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfan syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome Benign:1

Aug 18, 2011

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Thoracic aortic aneurysm Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs1155705; hg19: chr3-30686414; COSMIC: COSV55442809;