9-127826641-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA202695/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 49 hom. )

Consequence

ENG
NM_001278138.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: -0.0560

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278138.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENG	NM_001114753.3	MANE Select	c.392C>T	p.Pro131Leu	missense	Exon 4 of 15	NP_001108225.1	P17813-1
ENG	NM_001278138.2		c.-155C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001265067.1	F5GX88
ENG	NM_000118.4		c.392C>T	p.Pro131Leu	missense	Exon 4 of 14	NP_000109.1	Q5T9B9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENG	ENST00000373203.9	TSL:1 MANE Select	c.392C>T	p.Pro131Leu	missense	Exon 4 of 15	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.5	TSL:1	c.392C>T	p.Pro131Leu	missense	Exon 4 of 14	ENSP00000341917.3	P17813-2
ENG	ENST00000480266.7	TSL:2	c.-155C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	ENSP00000479015.1	F5GX88

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00461

AC:

1158

AN:

251006

AF XY:

0.00590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00274

AC:

4012

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

2510

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33478

American (AMR)

AF:

0.00143

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

336

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0253

AC:

2179

AN:

86244

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00753

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00100

AC:

1115

AN:

1111968

Other (OTH)

AF:

0.00412

AC:

249

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

242

484

726

968

1210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00193

AC:

293

AN:

152200

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41522

American (AMR)

AF:

0.00111

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

68004

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.00184

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00511

AC:

621

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00231

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Telangiectasia, hereditary hemorrhagic, type 1 (3)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Galloway-Mowat syndrome 1 (1)

Haemorrhagic telangiectasia 1 (1)

Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

2.8

(source)

DANN

Benign

0.60

DEOGEN2

Uncertain

0.48

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

-0.056

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.32

Sift

Benign

0.12

Sift4G

Benign

0.25

Polyphen

0.066

Vest4

0.11

MVP

0.96

MPC

0.22

ClinPred

0.020

GERP RS

-1.9

Varity_R

0.22

gMVP

0.16

Mutation Taster

=95/5

polymorphism

(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