Genetic Variant TGFBR1:p.Ala26dup (chr9-99105255-T-TGGC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_004612.4(TGFBR1):c.76_78dupGCG(p.Ala26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,043,488 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12O:1

Conservation

PhyloP100: 0.987

Publications

24 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004612.4

BP6

Variant 9-99105255-T-TGGC is Benign according to our data. Variant chr9-99105255-T-TGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213864.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000856 (122/142522) while in subpopulation SAS AF = 0.0026 (12/4608). AF 95% confidence interval is 0.0015. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 122 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	NM_004612.4	MANE Select	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	NP_004603.1	P36897-1
TGFBR1	NM_001306210.2		c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	NP_001293139.1	P36897-2
TGFBR1	NM_001407416.1		c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 8	NP_001394345.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000364133.4	P36897-1
TGFBR1	ENST00000552516.5	TSL:1	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000447297.1	P36897-2
TGFBR1	ENST00000374990.6	TSL:1	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes

AF:

0.000857

AC:

122

AN:

142420

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000689

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00227

Gnomad SAS

AF:

0.00260

Gnomad FIN

AF:

0.000614

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000928

Gnomad OTH

AF:

0.00153

GnomAD2 exomes

AF:

0.00171

AC:

AN:

584

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00139

AC:

1255

AN:

900966

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

596

AN XY:

422760

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

17388

American (AMR)

AF:

0.000713

AC:

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.000137

AC:

AN:

7300

East Asian (EAS)

AF:

0.00109

AC:

AN:

9216

South Asian (SAS)

AF:

0.00205

AC:

AN:

18064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5144

Middle Eastern (MID)

AF:

0.00154

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.00140

AC:

1130

AN:

807766

Other (OTH)

AF:

0.00166

AC:

AN:

31332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.000856

AC:

122

AN:

142522

Hom.:

Cov.:

AF XY:

0.000879

AC XY:

AN XY:

69398

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

39328

American (AMR)

AF:

0.000275

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00228

AC:

AN:

4822

South Asian (SAS)

AF:

0.00260

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.000614

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000928

AC:

AN:

64622

Other (OTH)

AF:

0.00151

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000611

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Familial thoracic aortic aneurysm and aortic dissection (3)

Multiple self-healing squamous epithelioma (1)

TGFBR1-related disorder (1)

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.99

Mutation Taster

=73/27

polymorphism

(source)

Splicing

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