rs11568778

chr9-99138128-A-Gchr9-99138128-A-T

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.805+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,549,336 control chromosomes in the GnomAD database, including 5,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (591 hom., cov: 32)
  • Exomes 𝑓: 0.026 (4463 hom.)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.83

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=-0.84).
• BP6: Variant 9-99138128-A-G is Benign according to our data. Variant chr9-99138128-A-G is described in ClinVar as [Benign]. Clinvar id is 259453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.805+39A>G		intron_variant		ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.805+39A>G		intron_variant		1	NM_004612.4	P4

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4869 AN: 152174 Hom.: 594 Cov.: 32

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0665 AC: 16409 AN: 246870 Hom.: 2208 AF XY: 0.0635 AC XY: 8497 AN XY: 133776

Gnomad AFR exome AF: 0.00570

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.429

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0256 AC: 35779 AN: 1397042 Hom.: 4463 Cov.: 22 AF XY: 0.0273 AC XY: 19054 AN XY: 698608

Gnomad4 AFR exome AF: 0.00524

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0320 AC: 4869 AN: 152294 Hom.: 591 Cov.: 32 AF XY: 0.0371 AC XY: 2762 AN XY: 74458

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0167 Hom.: 72

Bravo AF: 0.0375

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 10, 2018	- -
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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

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	-0.84
Cadd	Benign	6.9
Dann	Benign	0.73

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: rs11568778; hg19: chr9-101900410; COSMIC: COSV66627100; COSMIC: COSV66627100;