rs377548944

Positions:

• chr9-127825704-T-A
• chr9-127825704-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001114753.3(ENG):​c.680A>T​(p.His227Leu) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.105356395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.680A>T	p.His227Leu	missense_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.680A>T	p.His227Leu	missense_variant	5/14		NP_000109.1
ENG	NM_001278138.2	c.134A>T	p.His45Leu	missense_variant	5/15		NP_001265067.1
ENG	NM_001406715.1	c.680A>T	p.His227Leu	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.680A>T	p.His227Leu	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.680A>T	p.His227Leu	missense_variant	5/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.134A>T	p.His45Leu	missense_variant	5/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Uncertain	0.71	D;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;.;N
REVEL	Benign	0.023
Sift	Benign	0.40	T;.;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.27		Loss of disorder (P = 0.0488);.;Loss of disorder (P = 0.0488);
MVP		0.16
MPC		0.26
ClinPred		0.026	T
GERP RS		1.5
Varity_R		0.13
gMVP		0.45

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: rs377548944; hg19: chr9-130587983;