9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGC

Position:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004612.4(TGFBR1):​c.76_78del​(p.Ala26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,041,918 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (18 hom., cov: 30)
  • Exomes 𝑓: 0.00084 (6 hom.)
• Consequence: TGFBR1 NM_004612.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.84

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 -16 ACMG points.

• BP6: Variant 9-99105255-TGGC-T is Benign according to our data. Variant chr9-99105255-TGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in Lovd as [Benign]. Variant chr9-99105255-TGGC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00714 (1017/142520) while in subpopulation AFR AF= 0.0241 (948/39326). AF 95% confidence interval is 0.0228. There are 18 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.76_78del	p.Ala26del	inframe_deletion	1/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.76_78del	p.Ala26del	inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1001 AN: 142418 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00174

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.0000774

Gnomad OTH AF: 0.00612

GnomAD3 exomes AF: 0.00514 AC: 3 AN: 584 Hom.: 0 AF XY: 0.00588 AC XY: 2 AN XY: 340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000841 AC: 756 AN: 899398 Hom.: 6 AF XY: 0.000996 AC XY: 420 AN XY: 421838

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.000274

Gnomad4 EAS exome AF: 0.00142

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.00254

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00714 AC: 1017 AN: 142520 Hom.: 18 Cov.: 30 AF XY: 0.00718 AC XY: 498 AN XY: 69398

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00152

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000774

Gnomad4 OTH AF: 0.00605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 03, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs11466445; hg19: chr9-101867537;