Genetic Variant NM_004612.4:c.-26_-22dupGGGCC (chr9-99105165-C-CGGCCG) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_004612.4(TGFBR1):c.-26_-22dupGGGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 149,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TGFBR1
NM_004612.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.616

Publications

0 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 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

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 9-99105165-C-CGGCCG is Benign according to our data. Variant chr9-99105165-C-CGGCCG is described in ClinVar as [Benign]. Clinvar id is 1242739.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.-26_-22dupGGGCC		5_prime_UTR_variant	Exon 1 of 9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 link	c.-26_-22dupGGGCC		5_prime_UTR_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0000604

AC:

AN:

149000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000448

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000962

AC:

AN:

935552

Hom.:

Cov.:

AF XY:

0.0000847

AC XY:

AN XY:

436840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18706

American (AMR)

AF:

0.000798

AC:

AN:

3758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9310

East Asian (EAS)

AF:

0.000142

AC:

AN:

14036

South Asian (SAS)

AF:

0.000275

AC:

AN:

18196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8278

Middle Eastern (MID)

AF:

0.000458

AC:

AN:

2184

European-Non Finnish (NFE)

AF:

0.0000907

AC:

AN:

826896

Other (OTH)

AF:

0.000117

AC:

AN:

34188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000604

AC:

AN:

149108

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

72800

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41046

American (AMR)

AF:

0.000133

AC:

AN:

15036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.000197

AC:

AN:

5072

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

66908

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 15, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.62

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_004612.4:c.-26_-22dupGGGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over