rs1554810378

Positions:

• chr9-127825722-A-C
• chr9-127825722-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001114753.3(ENG):​c.662T>G​(p.Leu221Arg) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L221Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.99

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 10 ACMG points.

• PM1: In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 9-127825722-A-C is Pathogenic according to our data. Variant chr9-127825722-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1404505.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.662T>G	p.Leu221Arg	missense_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.662T>G	p.Leu221Arg	missense_variant	5/14		NP_000109.1
ENG	NM_001278138.2	c.116T>G	p.Leu39Arg	missense_variant	5/15		NP_001265067.1
ENG	NM_001406715.1	c.662T>G	p.Leu221Arg	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.662T>G	p.Leu221Arg	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.662T>G	p.Leu221Arg	missense_variant	5/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.116T>G	p.Leu39Arg	missense_variant	5/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu221 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10749981, 15880681, 16690726, 17384219, 21158752, 22991266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function. This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 221 of the ENG protein (p.Leu221Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.036	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.90
MutPred		0.74		Gain of disorder (P = 0.0209);.;Gain of disorder (P = 0.0209);
MVP		0.94
MPC		0.93
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130588001;