9-127825812-C-T

Variant names:

• chr9-127825812-C-T
• rs41322046
• NM_001114753.3:c.572G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5 BA1

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.572G>A variant in ENG is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 191 (p.Gly191Asp). The filtering allele frequency (the lower threshold of the 95% CI of 1725/109328) of the c.572G>A variant in ENG is 0.01669 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). This variant has been observed in at least 2 patients with an alternate molecular basis for disease (patients also carry likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID:32573726, Internal lab contributors). The computational predictor REVEL gives a score of 0.275, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1, BP5 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA325327/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (171 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign reviewed by expert panel B:18
• Conservation: PhyloP100: 1.44
• Publications: 15 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hereditary hemorrhagic telangiectasia

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.572G>A	p.Gly191Asp	missense	Exon 5 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.572G>A	p.Gly191Asp	missense	Exon 5 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.26G>A	p.Gly9Asp	missense	Exon 5 of 15	NP_001265067.1	F5GX88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.572G>A	p.Gly191Asp	missense	Exon 5 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.572G>A	p.Gly191Asp	missense	Exon 5 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.572G>A	p.Gly191Asp	missense	Exon 5 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1479 AN: 152158 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00882 AC: 1897 AN: 215084 AF XY: 0.00878

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00916

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0143 AC: 20731 AN: 1445124 Hom.: 171 Cov.: 34 AF XY: 0.0138 AC XY: 9912 AN XY: 717402

African (AFR) AF: 0.00256 AC: 85 AN: 33162

American (AMR) AF: 0.00530 AC: 226 AN: 42660

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 253 AN: 25782

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38902

South Asian (SAS) AF: 0.00267 AC: 223 AN: 83654

European-Finnish (FIN) AF: 0.00332 AC: 169 AN: 50838

Middle Eastern (MID) AF: 0.00372 AC: 21 AN: 5652

European-Non Finnish (NFE) AF: 0.0172 AC: 19033 AN: 1104786

Other (OTH) AF: 0.0121 AC: 720 AN: 59688

GnomAD4 genome AF: 0.00971 AC: 1479 AN: 152276 Hom.: 9 Cov.: 32 AF XY: 0.00913 AC XY: 680 AN XY: 74454

African (AFR) AF: 0.00318 AC: 132 AN: 41556

American (AMR) AF: 0.00706 AC: 108 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0167 AC: 1138 AN: 67986

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0137 Hom.: 53

Bravo AF: 0.00911

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.00824 AC: 993

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	6	Telangiectasia, hereditary hemorrhagic, type 1 (6)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	ENG-related disorder (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.099	T
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.59
MPC		0.90
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.39
gMVP		0.70
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41322046; hg19: chr9-130588091; COSMIC: COSV61227245; COSMIC: COSV61227245;