rs200224304

Positions:

• chr9-99105204-C-T

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: -0.0340

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 -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.-2C>T		5_prime_UTR_variant	1/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.-2C>T		5_prime_UTR_variant	1/9	1	NM_004612.4	P4

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

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

Gnomad4 AFR exome AF: 0.00297

Gnomad4 AMR exome AF: 0.000816

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000767

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.000296

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

Gnomad4 AFR AF: 0.00471

Gnomad4 AMR AF: 0.00114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000151

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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)	Jun 23, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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: rs200224304; hg19: chr9-101867486;