dbSNP rs200224304: TGFBR1:c.-2C>T (chr9-99105204-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0340

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD, Unknown 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
multiple self-healing squamous epithelioma
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFBR1	NM_004612.4	MANE Select	c.-2C>T	5_prime_UTR	Exon 1 of 9	NP_004603.1	P36897-1
TGFBR1	NM_001306210.2		c.-2C>T	5_prime_UTR	Exon 1 of 9	NP_001293139.1	P36897-2
TGFBR1	NM_001407416.1		c.-2C>T	5_prime_UTR	Exon 1 of 8	NP_001394345.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.-2C>T	5_prime_UTR	Exon 1 of 9	ENSP00000364133.4	P36897-1
TGFBR1	ENST00000552516.5	TSL:1	c.-2C>T	5_prime_UTR	Exon 1 of 9	ENSP00000447297.1	P36897-2
TGFBR1	ENST00000374990.6	TSL:1	c.-2C>T	5_prime_UTR	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

211

AN:

147236

Hom.:

Cov.:

show subpopulations

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:

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:

AN:

935516

Hom.:

Cov.:

AF XY:

0.0000775

AC XY:

AN XY:

438966

show subpopulations

African (AFR)

AF:

0.00297

AC:

AN:

18514

American (AMR)

AF:

0.000816

AC:

AN:

3676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8860

East Asian (EAS)

AF:

0.0000767

AC:

AN:

13032

South Asian (SAS)

AF:

0.00

AC:

AN:

18266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2172

European-Non Finnish (NFE)

AF:

0.00000241

AC:

AN:

829106

Other (OTH)

AF:

0.000296

AC:

AN:

33798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00145

AC:

213

AN:

147338

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

105

AN XY:

71896

show subpopulations

African (AFR)

AF:

0.00471

AC:

191

AN:

40538

American (AMR)

AF:

0.00114

AC:

AN:

14880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66346

Other (OTH)

AF:

0.00196

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000902

Hom.:

Bravo

AF:

0.00159

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

Multiple self-healing squamous epithelioma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

-0.034

PromoterAI

0.17

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Mutation Taster

=296/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over