Genetic Variant NM_004612.4:c.575-2409A>G (chr9-99135450-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004612.4(TGFBR1):c.575-2409A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0709 in 152,246 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.071 ( 467 hom., cov: 31)

Consequence

TGFBR1
NM_004612.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.650

Publications

17 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):

Loeys-Dietz syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Loeys-Dietz syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
multiple self-healing squamous epithelioma
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TGFBR1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004612.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

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.575-2409A>G	intron	N/A	NP_004603.1	P36897-1
TGFBR1	NM_001306210.2		c.587-2409A>G	intron	N/A	NP_001293139.1	P36897-2
TGFBR1	NM_001407416.1		c.587-2409A>G	intron	N/A	NP_001394345.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.575-2409A>G	intron	N/A	ENSP00000364133.4	P36897-1
TGFBR1	ENST00000552516.5	TSL:1	c.587-2409A>G	intron	N/A	ENSP00000447297.1	P36897-2
TGFBR1	ENST00000374990.6	TSL:1	c.344-2409A>G	intron	N/A	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes

AF:

0.0709

AC:

10792

AN:

152128

Hom.:

468

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0548

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0553

Gnomad ASJ

AF:

0.0723

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0346

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0843

Gnomad OTH

AF:

0.0788

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0709

AC:

10797

AN:

152246

Hom.:

467

Cov.:

AF XY:

0.0714

AC XY:

5311

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0548

AC:

2276

AN:

41546

American (AMR)

AF:

0.0552

AC:

845

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0723

AC:

251

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0348

AC:

168

AN:

4822

European-Finnish (FIN)

AF:

0.118

AC:

1252

AN:

10590

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0843

AC:

5734

AN:

68010

Other (OTH)

AF:

0.0780

AC:

165

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

527

1053

1580

2106

2633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0197

Hom.:

Bravo

AF:

0.0667

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.44

(source)

DANN

Benign

0.50

PhyloP100

-0.65

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over