9-127825701-G-T

Position:

• chr9-127825701-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.683C>A​(p.Ser228*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,586 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.59

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 12 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 9-127825701-G-T is Pathogenic according to our data. Variant chr9-127825701-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 528071.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.683C>A	p.Ser228*	stop_gained	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.683C>A	p.Ser228*	stop_gained	5/14		NP_000109.1
ENG	NM_001278138.2	c.137C>A	p.Ser46*	stop_gained	5/15		NP_001265067.1
ENG	NM_001406715.1	c.683C>A	p.Ser228*	stop_gained	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.683C>A	p.Ser228*	stop_gained	5/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.683C>A	p.Ser228*	stop_gained	5/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.137C>A	p.Ser46*	stop_gained	5/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430586 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 709250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This variant has not been reported in the literature in individuals with ENG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser228*) in the ENG gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Benign	0.96
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.018	N
Vest4		0.73
GERP RS		-3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1452543778; hg19: chr9-130587980;