9-127825701-G-T

Variant names:

• chr9-127825701-G-T
• rs1452543778
• NM_001114753.3:c.683C>A

Variant summary

Our verdict is Pathogenic. The variant received 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 (★). Synonymous variant affecting the same amino acid position (i.e. S228S) has been classified as Likely benign. 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
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 528071.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.683C>A	p.Ser228*	stop_gained	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 43060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25030

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39054

South Asian (SAS) AF: 0.00 AC: 0 AN: 83298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099856

Other (OTH) AF: 0.00 AC: 0 AN: 59064

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Nov 23, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.0	.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		-1.6
PROVEAN	Benign	0.0	.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.73
GERP RS		-3.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1452543778; hg19: chr9-130587980;