rs863223537

Positions:

• chr9-127825822-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.562C>T​(p.Gln188Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q188Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.762

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127825822-G-A is Pathogenic according to our data. Variant chr9-127825822-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 213211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127825822-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.562C>T	p.Gln188Ter	stop_gained	5/15	ENST00000373203.9
ENG	NM_000118.4	c.562C>T	p.Gln188Ter	stop_gained	5/14
ENG	NM_001278138.2	c.16C>T	p.Gln6Ter	stop_gained	5/15
ENG	NM_001406715.1	c.562C>T	p.Gln188Ter	stop_gained	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.562C>T	p.Gln188Ter	stop_gained	5/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.562C>T	p.Gln188Ter	stop_gained	5/14	1		A2
ENG	ENST00000480266.6	c.16C>T	p.Gln6Ter	stop_gained	5/15	2
ENG	ENST00000462196.1	n.462C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445698 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 717786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 21, 2021	PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2016	The Q188X pathogenic variant in the ENG gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Q188X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the ENG gene have been reported in association with HHT. In summary, Q188X in the ENG gene is interpreted as a pathogenic variant. This variant was found in HHT-PANCARD -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

The p.Q188* pathogenic mutation (also known as c.562C>T), located in coding exon 5 of the ENG gene, results from a C to T substitution at nucleotide position 562. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2018

This sequence change creates a premature translational stop signal (p.Gln188*) in the ENG gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ENG-related disease. ClinVar contains an entry for this variant (Variation ID: 213211). Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Benign	0.97
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.26	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.83
GERP RS		-8.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223537; hg19: chr9-130588101;