Genetic Variant ENG:c.1687-117G>A (chr9-127817320-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001114753.3(ENG):c.1687-117G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 997,594 control chromosomes in the GnomAD database, including 69,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8371 hom., cov: 32)

Exomes 𝑓: 0.37 ( 61197 hom. )

Consequence

ENG
NM_001114753.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.429

Publications

9 publications found

Variant links:

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ENG Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile polyposis syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENG links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 9-127817320-C-T is Benign according to our data. Variant chr9-127817320-C-T is described in ClinVar as Benign. ClinVar VariationId is 439656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENG	NM_001114753.3	MANE Select	c.1687-117G>A	intron	N/A	NP_001108225.1	P17813-1
ENG	NM_000118.4		c.1687-117G>A	intron	N/A	NP_000109.1	Q5T9B9
ENG	NM_001278138.2		c.1141-117G>A	intron	N/A	NP_001265067.1	F5GX88

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENG	ENST00000373203.9	TSL:1 MANE Select	c.1687-117G>A	intron	N/A	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.5	TSL:1	c.1687-117G>A	intron	N/A	ENSP00000341917.3	P17813-2
ENG	ENST00000714047.1		c.1687-117G>A	intron	N/A	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

45148

AN:

151950

Hom.:

8378

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0762

Gnomad AMI

AF:

0.485

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.351

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.307

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.384

Gnomad OTH

AF:

0.326

GnomAD4 exome

AF:

0.370

AC:

312816

AN:

845526

Hom.:

61197

Cov.:

AF XY:

0.368

AC XY:

161937

AN XY:

439578

show subpopulations

African (AFR)

AF:

0.0686

AC:

1471

AN:

21448

American (AMR)

AF:

0.415

AC:

14874

AN:

35824

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

7292

AN:

21688

East Asian (EAS)

AF:

0.602

AC:

20703

AN:

34364

South Asian (SAS)

AF:

0.302

AC:

20853

AN:

68946

European-Finnish (FIN)

AF:

0.315

AC:

15121

AN:

48062

Middle Eastern (MID)

AF:

0.338

AC:

1557

AN:

4612

European-Non Finnish (NFE)

AF:

0.380

AC:

216804

AN:

570572

Other (OTH)

AF:

0.353

AC:

14141

AN:

40010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

10492

20984

31477

41969

52461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4616

9232

13848

18464

23080

<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:

0.297

AC:

45143

AN:

152068

Hom.:

8371

Cov.:

AF XY:

0.295

AC XY:

21927

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0760

AC:

3157

AN:

41542

American (AMR)

AF:

0.378

AC:

5773

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.351

AC:

1218

AN:

3468

East Asian (EAS)

AF:

0.583

AC:

3002

AN:

5152

South Asian (SAS)

AF:

0.301

AC:

1451

AN:

4816

European-Finnish (FIN)

AF:

0.307

AC:

3244

AN:

10570

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.384

AC:

26065

AN:

67952

Other (OTH)

AF:

0.325

AC:

685

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1488

2976

4464

5952

7440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.343

Hom.:

2310

Bravo

AF:

0.298

Asia WGS

AF:

0.376

AC:

1309

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Telangiectasia, hereditary hemorrhagic, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.0

(source)

DANN

Benign

0.58

PhyloP100

-0.43

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

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