9-127854354-A-G

Position:

• chr9-127854354-A-G

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.2T>C​(p.Met1?) variant causes a start lost 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENG NM_001114753.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.64

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 Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127854354-A-G is Pathogenic according to our data. Variant chr9-127854354-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 16673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.2T>C	p.Met1?	start_lost	1/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.2T>C	p.Met1?	start_lost	1/14		NP_000109.1
ENG	NM_001406715.1	c.2T>C	p.Met1?	start_lost	1/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.2T>C	p.Met1?	start_lost	1/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.2T>C	p.Met1?	start_lost	1/14	1		ENSP00000341917	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The start-lost variant c.2T>C(p.Met1?) in the ENG gene has been reported previously in a heterozygous state in individuals affected with hereditary hemorrhagic telangiectasia (HHT). A T-to-C transition converts ATG (Met) to ACG (Thr) thereby causing a start loss (Gallione et al., 1998; Abdalla et al., 2006). This variant is reported with the allele frequency (0.002%) in the gnomAD and novel in 1000 genome database. It is submitted to ClinVar as Pathogenic. The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. The variant is predicted as damaging by SIFT. The amino acid change p.Met1? in ENG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2016

The p.M1? pathogenic variant (also known as c.2T>C and p.M1T), located in coding exon 1 of the ENG gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This alteration was identified in 2 unrelated individuals with hereditary hemorrhagic telangiectasia (HHT) (Gallione et al. J Hum Mutat. 1998;11(4):286-94). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		1.0		Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);
MVP		0.90
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.86

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: rs267606783; hg19: chr9-130616633;