chr9-127825701-G-A

Position:

• chr9-127825701-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_001114753.3(ENG):​c.683C>T​(p.Ser228Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000979 in 1,430,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.59

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 -4 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.14168614).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.683C>T	p.Ser228Leu	missense_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.683C>T	p.Ser228Leu	missense_variant	5/14		NP_000109.1
ENG	NM_001278138.2	c.137C>T	p.Ser46Leu	missense_variant	5/15		NP_001265067.1
ENG	NM_001406715.1	c.683C>T	p.Ser228Leu	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.683C>T	p.Ser228Leu	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.683C>T	p.Ser228Leu	missense_variant	5/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.137C>T	p.Ser46Leu	missense_variant	5/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000976 AC: 2 AN: 204928 Hom.: 0 AF XY: 0.0000176 AC XY: 2 AN XY: 113372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000597

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.00000979 AC: 14 AN: 1430586 Hom.: 0 Cov.: 34 AF XY: 0.0000113 AC XY: 8 AN XY: 709250

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.0000227

Gnomad4 NFE exome AF: 0.00000546

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed missense c.683C>T(p.Ser228Leu) variant in ENG gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Ser228Leu variant has been reported with allele frequency of 0.001% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. The amino acid Ser at position 228 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.9
DANN	Benign	0.97
DEOGEN2	Uncertain	0.79	D;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.034
Sift	Benign	0.13	T;.;T
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.53	P;.;.
Vest4		0.22
MutPred		0.28		Loss of disorder (P = 0.0312);.;Loss of disorder (P = 0.0312);
MVP		0.50
MPC		0.20
ClinPred		0.34	T
GERP RS		-3.0
Varity_R		0.088
gMVP		0.43

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: rs1452543778; hg19: chr9-130587980;