Variant chr9-99105115-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_004612.4(TGFBR1):c.-91C>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 0.000417 in 986,194 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

TGFBR1
NM_004612.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.107

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 9-99105115-C-T is Benign according to our data. Variant chr9-99105115-C-T is described in ClinVar as [Benign]. Clinvar id is 2504011.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0018 (269/149432) while in subpopulation AFR AF= 0.00627 (257/40994). AF 95% confidence interval is 0.00564. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4 linkuse as main transcript	c.-91C>T		5_prime_UTR_variant	1/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 linkuse as main transcript	c.-91C>T		5_prime_UTR_variant	1/9	1	NM_004612.4	ENSP00000364133	P4	P36897-1

Frequencies

GnomAD3 genomes

AF:

0.00180

AC:

269

AN:

149324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000531

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:

0.0000298

Gnomad OTH

AF:

0.000978

GnomAD4 exome

AF:

0.000170

AC:

142

AN:

836762

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

389468

show subpopulations

Gnomad4 AFR exome

AF:

0.00724

Gnomad4 AMR exome

AF:

0.000383

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000268

Gnomad4 OTH exome

AF:

0.000534

GnomAD4 genome

AF:

0.00180

AC:

269

AN:

149432

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

129

AN XY:

73012

show subpopulations

Gnomad4 AFR

AF:

0.00627

Gnomad4 AMR

AF:

0.000530

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000299

Gnomad4 OTH

AF:

0.000968

Alfa

AF:

0.00142

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 03, 2023

Variant summary: TGFBR1 c.-91C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0019 in 28470 control chromosomes, predominantly at a frequency of 0.0063 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3360-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.-91C>T in individuals affected with Loeys-Dietz Syndrome or other TGFBR1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over