chr9-127854354-A-C

Position:

• chr9-127854354-A-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4 PM5_Strong PVS1_Strong PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.2T>G variant in ENG may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:12920067, 32300199, 15024723, ClinVar, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). Four different missense variants, c.3G>A, c.1A>T, c.2T>C, c.1A>G, in the same codon have been classified as pathogenic/likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PVS1_Strong, PS4, PP4_Moderate, PM5_Strong (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA374989708/MONDO:0008535/136

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENG NM_001114753.3 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel 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 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.2T>G	p.Met1?	start_lost	1/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.2T>G	p.Met1?	start_lost	1/14		NP_000109.1
ENG	NM_001406715.1	c.2T>G	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>G	p.Met1?	start_lost	1/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.2T>G	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: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Mar 15, 2024

The NM_001114753.3: c.2T>G variant in ENG may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:12920067, 32300199, 15024723, ClinVar, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). Four different missense variants, c.3G>A, c.1A>T, c.2T>C, c.1A>G, in the same codon have been classified as pathogenic/likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PVS1_Strong, PS4, PP4_Moderate, PM5_Strong (specification version 1.0.0; 1/4/2024). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2021

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12920067, 15024723, 9554745, 21158752, 32300199) -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 07, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 458346). Disruption of the initiator codon has been observed in individuals with hemorrhagic telangiectasia (PMID: 9554745, 12920067, 15517393, 20414677, 21158752). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.95
MutPred		0.99		Loss of stability (P = 0.0064);Loss of stability (P = 0.0064);
MVP		0.91
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.93

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;