rs199675436

Variant names:

• chr9-127843192-C-A
• NM_001114753.3:c.121G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-127843192-C-A
• chr9-127843192-C-G
• chr9-127843192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.121G>T​(p.Glu41*) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -4.13

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127843192-C-A is Pathogenic according to our data. Variant chr9-127843192-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1752821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.121G>T	p.Glu41*	stop_gained	Exon 2 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.121G>T	p.Glu41*	stop_gained	Exon 2 of 14		NP_000109.1
ENG	NM_001406715.1	c.121G>T	p.Glu41*	stop_gained	Exon 2 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-426G>T		5_prime_UTR_variant	Exon 2 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.121G>T	p.Glu41*	stop_gained	Exon 2 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.121G>T	p.Glu41*	stop_gained	Exon 2 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-426G>T		5_prime_UTR_variant	Exon 2 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Jun 29, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E41* pathogenic mutation (also known as c.121G>T), located in coding exon 2 of the ENG gene, results from a G to T substitution at nucleotide position 121. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This variant was reported in three affected individuals from a family with hereditary hemorrhagic telangiectasia (HHT) (Cymerman U et al. Hum Mutat, 2003 May;21:482-92). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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	0.010
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.012	N
Vest4		0.82
GERP RS		-1.9

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: chr9-130605471;