NM_001114753.3:c.-9G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BP5PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.-9G>A variant is located in the 5' UTR of ENG. Because the variant is located in the 5' UTR, is it not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007942 (76/95698 alleles) in the European (non-Finnish) population. This variant has been observed in patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ACVRL1 variant) (BP5; Internal lab contributors). Expression studies showed this variant causes a small reduction (~18.4%) of endoglin compared to wild type (PS3_Supporting, PMID:22192717). Due to conflicting evidence, this variant is classified as a variant of uncertain significance 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: PS3_Supporting, BP5 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5253269/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

ENG
NM_001114753.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:11B:3

Conservation

PhyloP100: 0.0650

Publications

6 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:

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ACMG classification

Specifications for ENG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PS3

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

BP5

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

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.-9G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001108225.1	P17813-1
ENG	NM_001114753.3	MANE Select	c.-9G>A	5_prime_UTR	Exon 1 of 15	NP_001108225.1	P17813-1
ENG	NM_000118.4		c.-9G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_000109.1	Q5T9B9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENG	ENST00000373203.9	TSL:1 MANE Select	c.-9G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.5	TSL:1	c.-9G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000341917.3	P17813-2
ENG	ENST00000373203.9	TSL:1 MANE Select	c.-9G>A	5_prime_UTR	Exon 1 of 15	ENSP00000362299.4	P17813-1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000517

AC:

AN:

191406

AF XY:

0.000524

show subpopulations

Gnomad AFR exome

AF:

0.000263

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000294

Gnomad NFE exome

AF:

0.000847

Gnomad OTH exome

AF:

0.000398

GnomAD4 exome

AF:

0.000815

AC:

1167

AN:

1431220

Hom.:

Cov.:

AF XY:

0.000822

AC XY:

583

AN XY:

709318

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

32730

American (AMR)

AF:

0.000174

AC:

AN:

40240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25516

East Asian (EAS)

AF:

0.00

AC:

AN:

37796

South Asian (SAS)

AF:

0.000722

AC:

AN:

81758

European-Finnish (FIN)

AF:

0.000196

AC:

AN:

50908

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000965

AC:

1059

AN:

1097416

Other (OTH)

AF:

0.000439

AC:

AN:

59160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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:

0.000414

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41458

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000620

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000758

Hom.:

Bravo

AF:

0.000408

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Telangiectasia, hereditary hemorrhagic, type 1 (5)

Hereditary hemorrhagic telangiectasia (2)

Cardiovascular phenotype (1)

ENG-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.065

PromoterAI

0.21

Neutral

(source)

Mutation Taster

=300/0

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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