NM_004612.4:c.73_78dupGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_004612.4(TGFBR1):c.73_78dupGCGGCG(p.Ala25_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 0.000159 in 1,043,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

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 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 -5 ACMG points.

BP6

Variant 9-99105255-T-TGGCGGC is Benign according to our data. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264. Variant chr9-99105255-T-TGGCGGC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496264.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	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.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

142424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000688

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.000434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000232

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000154

AC:

139

AN:

900968

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

422764

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000230

AC:

AN:

17388

American (AMR)

AF:

0.000357

AC:

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7300

East Asian (EAS)

AF:

0.00

AC:

AN:

9216

South Asian (SAS)

AF:

0.000498

AC:

AN:

18064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.000149

AC:

120

AN:

807768

Other (OTH)

AF:

0.000160

AC:

AN:

31332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000189

AC:

AN:

142526

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

AN XY:

69400

show subpopulations

African (AFR)

AF:

0.000178

AC:

AN:

39330

American (AMR)

AF:

0.0000687

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.000415

AC:

AN:

4824

South Asian (SAS)

AF:

0.000434

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000232

AC:

AN:

64622

Other (OTH)

AF:

0.00

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2Benign:1

Feb 21, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 13, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.73_78dup, results in the insertion of 2 amino acid(s) of the TGFBR1 protein (p.Ala25_Ala26dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496264). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1Benign:1

Jul 23, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Mar 30, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The TGFBR1 c.73_78dupGCGGCG (p.Ala25_Ala26dup) variant involves the duplication of six nucleotides in a repetitive region. One in silico tools predicts a deleterious outcome for this variant. The frequency of this variant in population databases is not available due to lack of coverage or very low coverage of the chromosomal region. This variant was reported to be found in 1/2436 control chromosomes in the literature at a frequency of 0.0004105, which is approximately 263 times the estimated maximal expected allele frequency of a pathogenic TGFBR1 variant (0.0000016), suggesting this variant is possibly a benign polymorphism, although the allele number is very low. This variant has been reported in a sporadic BrC patient without evidence of causality. The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available. -

Computational scores

Source: dbNSFP v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over