ENG p.Trp149Cys

Variant names:

• chr9-127826586-C-A
• NM_001114753.3:c.447G>T
• ENG p.Trp149Cys

Your query was ambiguous. Multiple possible variants found:

• chr9-127826586-C-A
• chr9-127826586-C-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1_Very_Strong PM2 PP3_Moderate

The NM_001114753.3(ENG):​c.447G>T​(p.Trp149Cys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 0 publications found

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]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for ENG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_001114753.3 (ENG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.447G>T	p.Trp149Cys	missense	Exon 4 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.447G>T	p.Trp149Cys	missense	Exon 4 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001406715.1		c.447G>T	p.Trp149Cys	missense	Exon 4 of 8	NP_001393644.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.447G>T	p.Trp149Cys	missense	Exon 4 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.447G>T	p.Trp149Cys	missense	Exon 4 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.447G>T	p.Trp149Cys	missense	Exon 4 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.79
gMVP		0.91
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-130588865;