9-127854355-T-C

Position:

• chr9-127854355-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000696 in 1,436,158 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.63

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001114753.3 (ENG) was described as [Pathogenic] in ClinVar as 458346
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127854355-T-C is Pathogenic according to our data. Variant chr9-127854355-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 407131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127854355-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1A>G	p.Met1?	start_lost	1/15	ENST00000373203.9
ENG	NM_000118.4	c.1A>G	p.Met1?	start_lost	1/14
ENG	NM_001406715.1	c.1A>G	p.Met1?	start_lost	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1A>G	p.Met1?	start_lost	1/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.1A>G	p.Met1?	start_lost	1/14	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436158 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712250

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 29, 2022	PVS1, PM2, PS4_moderate -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 17, 2017

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 407131). Disruption of the initiator codon has been observed in individuals with hereditary haemorrhagic telangiectasia (PMID: 15517393, 16429404, 32573726; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ENG mRNA. The next in-frame methionine is located at codon 183. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2020

The p.M1? pathogenic mutation (also known as c.1A>G and p.M1V) is located in coding exon 1 of the ENG gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration has been identified in multiple individuals with hereditary hemorrhagic telangiectasia, most of whom meet Curaçao criteria (Letteboer TG et al. Hum Genet. 2005; 116(1-2):8-16; Lenato GM et al. Hum Mutat. 2006; 27(2):213-4; Gedge F et al. J Mol Diagn. 2007; 9(2):258-65; Curie A et al. J. Pediatr. 2007; 151(3):299-306; Calhoun AR et al. J Neurosurg Pediatr 2012; 9(6):654-9; Eli I et al. J Clin Neurosci 2018; 50:51-57; Gamboa NT et al. J Clin Neurosci 2018; 51:22-28). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.96
MutPred		1.0		Loss of stability (P = 0.0961);Loss of stability (P = 0.0961);
MVP		0.92
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1060501418; hg19: chr9-130616634;