rs142896669

Variant names:

• chr9-127818173-C-T
• rs142896669
• NM_001114753.3:c.1633G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP5 BS1_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID:18498373) which is classified as likely pathogenic (PMID:18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, 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 likely 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: BS1_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252712/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:7
• Conservation: PhyloP100: 4.33
• Publications: 14 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

ENSG00000225032 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1633G>A	p.Gly545Ser	missense	Exon 12 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1633G>A	p.Gly545Ser	missense	Exon 12 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.1087G>A	p.Gly363Ser	missense	Exon 12 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.1633G>A	p.Gly545Ser	missense	Exon 12 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1633G>A	p.Gly545Ser	missense	Exon 12 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1633G>A	p.Gly545Ser	missense	Exon 12 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

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: 0.000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000521 AC: 131 AN: 251296 AF XY: 0.000456

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1461876 Hom.: 2 Cov.: 31 AF XY: 0.000660 AC XY: 480 AN XY: 727242

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000771 AC: 857 AN: 1112012

Other (OTH) AF: 0.000364 AC: 22 AN: 60394

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74476

African (AFR) AF: 0.000120 AC: 5 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000487 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Telangiectasia, hereditary hemorrhagic, type 1 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	ENG-related disorder (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	1	-	Pulmonary arterial hypertension associated with congenital heart disease (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.061	T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.057	T
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.48
MVP		0.88
MPC		0.76
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.64
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142896669; hg19: chr9-130580452; COSMIC: COSV61226765; COSMIC: COSV61226765;