NM_004612.4:c.1255+24G>A

Variant names:

• chr9-99146633-G-A
• rs334354
• NM_004612.4:c.1255+24G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 33 publications found

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]

TGFBR1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.1255+24G>A		intron_variant	Intron 7 of 8	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1255+24G>A		intron_variant	Intron 7 of 8	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

GnomAD2 exomes AF: 0.221 AC: 55348 AN: 251002 AF XY: 0.218

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 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

African (AFR) AF: 0.250 AC: 8375 AN: 33436

American (AMR) AF: 0.230 AC: 10304 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5184 AN: 26114

East Asian (EAS) AF: 0.480 AC: 19035 AN: 39662

South Asian (SAS) AF: 0.223 AC: 19260 AN: 86248

European-Finnish (FIN) AF: 0.143 AC: 7646 AN: 53396

Middle Eastern (MID) AF: 0.178 AC: 1027 AN: 5760

European-Non Finnish (NFE) AF: 0.201 AC: 223428 AN: 1111386

Other (OTH) AF: 0.219 AC: 13220 AN: 60352

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

African (AFR) AF: 0.250 AC: 10375 AN: 41466

American (AMR) AF: 0.244 AC: 3722 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 693 AN: 3472

East Asian (EAS) AF: 0.432 AC: 2230 AN: 5168

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4828

European-Finnish (FIN) AF: 0.143 AC: 1517 AN: 10582

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13812 AN: 67996

Other (OTH) AF: 0.221 AC: 467 AN: 2110

Alfa AF: 0.211 Hom.: 1385

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

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported.

not provided Benign:3

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15382067, 22905183, 20354825, 16428477)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome 1 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Multiple self-healing squamous epithelioma Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.14
DANN	Benign	0.69
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs334354; hg19: chr9-101908915; COSMIC: COSV66626472; COSMIC: COSV66626472;