9-127829725-GC-AA

Position:

• chr9-127829725-GC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001114753.3(ENG):​c.321_322delinsTT​(p.His108Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L107L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.400

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.321_322delinsTT	p.His108Tyr	missense_variant	3/15	ENST00000373203.9
ENG	NM_000118.4	c.321_322delinsTT	p.His108Tyr	missense_variant	3/14
ENG	NM_001406715.1	c.321_322delinsTT	p.His108Tyr	missense_variant	3/8
ENG	NM_001278138.2	c.-226_-225delinsTT		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.321_322delinsTT	p.His108Tyr	missense_variant	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.321_322delinsTT	p.His108Tyr	missense_variant	3/14	1		A2
ENG	ENST00000480266.6	c.-226_-225delinsTT		5_prime_UTR_variant	3/15	2
ENG	ENST00000462196.1	n.79_80delinsTT		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.His108Tyr (c. 321_322delinsTT) variant in ENG results from a deletion and insertion of 2 conse cutive bases in cis and creates a missense change. This variant has been reporte d in 1 French individual with Hereditary Hemorrhagic Telangiectasia (HHT); howev er, this individual carried a second variant in ENG that was sufficient to expla in their disease (Mallet 2015). The p.His108Tyr variant has also been identified in 15/66242 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs756897517). In vitro functional studies pro vide some evidence that this change may not impact protein function (Mallet 2015 ). However, these types of assays may not accurately represent biological functi on. In summary, while the clinical significance of the p.His108Tyr variant is un certain, these data suggest that it is more likely to be benign. -

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 28, 2022

- -

Hereditary hemorrhagic telangiectasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 108 of the ENG protein (p.His108Tyr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 25312062). ClinVar contains an entry for this variant (Variation ID: 407139). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change does not substantially affect ENG function (PMID: 25312062). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501425; hg19: chr9-130592004;