9-127815951-G-A

Variant names:

• chr9-127815951-G-A
• rs148002300
• NM_001114753.3:c.1844C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1 BP5 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID:15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID:25312062, 22022569). 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, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211415/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:16
• Conservation: PhyloP100: 2.10
• Publications: 16 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 -6 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.1844C>T	p.Ser615Leu	missense	Exon 14 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1844C>T	p.Ser615Leu	missense	Exon 14 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.1298C>T	p.Ser433Leu	missense	Exon 14 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.1844C>T	p.Ser615Leu	missense	Exon 14 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1844C>T	p.Ser615Leu	missense	Exon 14 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1844C>T	p.Ser615Leu	missense	Exon 14 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00154 AC: 345 AN: 224358 AF XY: 0.00153

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000592

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00206 AC: 2985 AN: 1447230 Hom.: 2 Cov.: 31 AF XY: 0.00202 AC XY: 1452 AN XY: 718594

African (AFR) AF: 0.000419 AC: 14 AN: 33378

American (AMR) AF: 0.000472 AC: 20 AN: 42346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.000281 AC: 11 AN: 39180

South Asian (SAS) AF: 0.000955 AC: 80 AN: 83796

European-Finnish (FIN) AF: 0.00144 AC: 74 AN: 51484

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.00245 AC: 2704 AN: 1105776

Other (OTH) AF: 0.00135 AC: 81 AN: 59848

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74492

African (AFR) AF: 0.000529 AC: 22 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00203 Hom.: 2

Bravo AF: 0.00133

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00129 AC: 156

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Telangiectasia, hereditary hemorrhagic, type 1 (6)
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Haemorrhagic telangiectasia 1 (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.19
Sift	Benign	0.065	T
Sift4G	Uncertain	0.053	T
Polyphen		0.11	B
Vest4		0.81
MVP		0.83
MPC		0.23
ClinPred		0.040	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.71
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs148002300; hg19: chr9-130578230;