rs334354

Positions:

• chr9-99146633-G-A
• chr9-99146633-G-C

Variant summary

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

The NM_004612.4(TGFBR1):​c.1255+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,613,174 control chromosomes in the GnomAD database, including 38,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4034 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34404 hom.)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.759

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 9-99146633-G-A is Benign according to our data. Variant chr9-99146633-G-A is described in ClinVar as [Benign]. Clinvar id is 259451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99146633-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.1255+24G>A		intron_variant		ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1255+24G>A		intron_variant		1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34035 AN: 151990 Hom.: 4020 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.221 AC: 55348 AN: 251002 Hom.: 6721 AF XY: 0.218 AC XY: 29571 AN XY: 135650

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.442

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.210 AC: 307479 AN: 1461066 Hom.: 34404 Cov.: 34 AF XY: 0.211 AC XY: 153060 AN XY: 726882

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.219

GnomAD4 genome AF: 0.224 AC: 34091 AN: 152108 Hom.: 4034 Cov.: 32 AF XY: 0.222 AC XY: 16490 AN XY: 74380

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.221

Alfa AF: 0.213 Hom.: 918

Bravo AF: 0.230

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	This variant is associated with the following publications: (PMID: 15382067, 22905183, 20354825, 16428477) -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Loeys-Dietz syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Multiple self-healing squamous epithelioma Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.14
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs334354; hg19: chr9-101908915; COSMIC: COSV66626472; COSMIC: COSV66626472;