rs200224304

Variant names:

• chr9-99105204-C-T
• rs200224304
• NM_004612.4:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004612.4(TGFBR1):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,082,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (1 hom.)
• Consequence: TGFBR1 NM_004612.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0340
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 9-99105204-C-T is Benign according to our data. Variant chr9-99105204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00145 (213/147338) while in subpopulation AFR AF = 0.00471 (191/40538). AF 95% confidence interval is 0.00416. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.-2C>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.-2C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 211 AN: 147236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.00 AC: 0 AN: 318 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000759 AC: 71 AN: 935516 Hom.: 1 Cov.: 30 AF XY: 0.0000775 AC XY: 34 AN XY: 438966

African (AFR) AF: 0.00297 AC: 55 AN: 18514

American (AMR) AF: 0.000816 AC: 3 AN: 3676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8860

East Asian (EAS) AF: 0.0000767 AC: 1 AN: 13032

South Asian (SAS) AF: 0.00 AC: 0 AN: 18266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2172

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 829106

Other (OTH) AF: 0.000296 AC: 10 AN: 33798

GnomAD4 genome AF: 0.00145 AC: 213 AN: 147338 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 105 AN XY: 71896

African (AFR) AF: 0.00471 AC: 191 AN: 40538

American (AMR) AF: 0.00114 AC: 17 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66346

Other (OTH) AF: 0.00196 AC: 4 AN: 2044

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 23, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 04, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.-2C>T variant substitutes a non-conserved nucleotide in the 5-prime untranslated region. The variant falls within the Kozak's sequence (gcc)gccRccAUGG; however, it does not involve the conserved nuncleotides in the sequence (AUGG and R are known to be highly conserved). This variant was found in 11/5008 chromosomes from Thousands Genomes Project at a frequency of 0.0021965, which is more than 1756 times greater than the maximal expected frequency of a pathogenic allele (0.0000013) in this gene (based on the disease prevalence of Aortopathy), suggesting this variant is benign. [The frequency data from NHLBI ESP and ExAC were not applicable either due to extremely low coverage or the nucleotide position not being covered.] The variant has not been reported in affected patients via literature. Two clinical labs (via ClinVar) have classified this variant as likely benign. Taken together, this variant as been classified as Benign. -

Dec 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Apr 23, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Multiple self-healing squamous epithelioma Benign:1

Feb 01, 2025

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	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
PhyloP100		-0.034
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

dbSNP: rs200224304; hg19: chr9-101867486;