rs774709924

Positions:

• chr9-127824952-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_001114753.3(ENG):​c.839A>G​(p.Lys280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a disulfide_bond (size 88) in uniprot entity EGLN_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001114753.3
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.839A>G	p.Lys280Arg	missense_variant	7/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.839A>G	p.Lys280Arg	missense_variant	7/14		NP_000109.1
ENG	NM_001278138.2	c.293A>G	p.Lys98Arg	missense_variant	7/15		NP_001265067.1
ENG	NM_001406715.1	c.839A>G	p.Lys280Arg	missense_variant	7/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.839A>G	p.Lys280Arg	missense_variant	7/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.839A>G	p.Lys280Arg	missense_variant	7/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.293A>G	p.Lys98Arg	missense_variant	7/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251172 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2018

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. This sequence change replaces lysine with arginine at codon 280 of the ENG protein (p.Lys280Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs774709924, ExAC 0.003%). This variant has not been reported in the literature in individuals with ENG-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.23
Sift	Benign	0.53	T;.;T
Sift4G	Benign	0.38	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.35
MutPred		0.66		Loss of methylation at K280 (P = 0.0082);.;Loss of methylation at K280 (P = 0.0082);
MVP		0.79
MPC		0.73
ClinPred		0.58	D
GERP RS		4.2
Varity_R		0.17
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs774709924; hg19: chr9-130587231;