NM_001114753.3:c.511C>T

Variant names:

• chr9-127826522-G-A
• rs1554810490
• NM_001114753.3:c.511C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.511C>T​(p.Arg171*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000603445: "In vitro functional analyses demonstrate diminished upregulation of endoglin during monocyte activation (Sanz-Rodriguez 2004)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R171R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.76
• Publications: 2 publications found

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

ACMG classification

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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000603445: "In vitro functional analyses demonstrate diminished upregulation of endoglin during monocyte activation (Sanz-Rodriguez 2004)."; SCV000748207: Published functional studies demonstrate that the variant results in premature mRNA degradation (Shovlin et al., 1997) and diminishes endoglin up-regulation in activated monocytes (Sanz-Rodriguez et al., 2004); SCV002642220: analysis of cultured peripheral blood mononuclear cells derived from two affected individuals showed significantly decreased upregulation of the ENG gene compared to an unaffected relative (Sanz-Rodriguez F et al. Clin Chem. 2004;50(11):2003-2011).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127826522-G-A is Pathogenic according to our data. Variant chr9-127826522-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 439644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.511C>T	p.Arg171*	stop_gained	Exon 4 of 15	NP_001108225.1	P17813-1
	ENG	NM_001278138.2		c.-36C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001265067.1	F5GX88
	ENG	NM_000118.4		c.511C>T	p.Arg171*	stop_gained	Exon 4 of 14	NP_000109.1	Q5T9B9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.511C>T	p.Arg171*	stop_gained	Exon 4 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.511C>T	p.Arg171*	stop_gained	Exon 4 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000480266.7	TSL:2	c.-36C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	ENSP00000479015.1	F5GX88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (5)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	ENG-related disorder (1)
1	-	-	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		3.8
Vest4		0.84
GERP RS		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554810490; hg19: chr9-130588801; COSMIC: COSV61227618; COSMIC: COSV61227618;