rs201393380

Positions:

• chr9-127825767-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001114753.3(ENG):​c.617G>C​(p.Gly206Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,598,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G206G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (1 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03391394).
• BP6: Variant 9-127825767-C-G is Benign according to our data. Variant chr9-127825767-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 407133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000684 (104/152100) while in subpopulation AFR AF= 0.00249 (103/41412). AF 95% confidence interval is 0.0021. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.617G>C	p.Gly206Ala	missense_variant	5/15	ENST00000373203.9
ENG	NM_000118.4	c.617G>C	p.Gly206Ala	missense_variant	5/14
ENG	NM_001278138.2	c.71G>C	p.Gly24Ala	missense_variant	5/15
ENG	NM_001406715.1	c.617G>C	p.Gly206Ala	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.617G>C	p.Gly206Ala	missense_variant	5/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.617G>C	p.Gly206Ala	missense_variant	5/14	1		A2
ENG	ENST00000480266.6	c.71G>C	p.Gly24Ala	missense_variant	5/15	2
ENG	ENST00000462196.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 27 AN: 213024 Hom.: 0 AF XY: 0.0000855 AC XY: 10 AN XY: 117000

Gnomad AFR exome AF: 0.00222

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000581 AC: 84 AN: 1446558 Hom.: 1 Cov.: 34 AF XY: 0.0000432 AC XY: 31 AN XY: 718338

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.0000465

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000838

GnomAD4 genome AF: 0.000684 AC: 104 AN: 152100 Hom.: 1 Cov.: 32 AF XY: 0.000700 AC XY: 52 AN XY: 74278

Gnomad4 AFR AF: 0.00249

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000756

ExAC AF: 0.000295 AC: 35

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 02, 2018

The ENG c.617G>C; p.Gly206Ala variant (rs201393380), is reported in the literature in an individual with features of HHT but not a definitive diagnosis (Mallet 2015), and the variant did not co-segregate with disease in this family. Functional studies of the variant protein show normal localization to the cell surface and a normal BMP9 response (Mallet 2015). This variant is reported in ClinVar (Variation ID: 407133). It is found in the African population with an allele frequency of 0.3% (28/8684 alleles) in the Genome Aggregation Database. The glycine at codon 206 is well conserved, but computational algorithms (SIFT: Damaging, PolyPhen2: Benign) predict conflicting effects of this variant on the protein. Based on available information, this variant is considered likely benign. REFERENCES Mallet C et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet. 2015 Feb 15;24(4):1142-54. -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.025	D;.;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.91	P;.;.
Vest4		0.47
MVP		0.69
MPC		0.36
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.63
gMVP		0.76

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: rs201393380; hg19: chr9-130588046;