rs1060501410

Variant names:

• chr9-127824800-C-T
• rs1060501410
• NM_001114753.3:c.991G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2_Supporting PS4 PS3 PP1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.991G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 331 (p.Gly331Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID:19767588, 34872578, 16690726, 34880085, 15517393, 25970827, 29171923, 32573726, 21158752, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID:19767588, 21158752). The variant has been reported to segregate with HHT in 3 affected meioses from 2 families (PP1; PMID:19767588, 34872578). The computational predictor REVEL gives a score of 0.202, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, RT-PCR analysis of cDNA demonstrated that the variant impacts splicing by leading to exon 7 skipping (PS3; PMID:16690726). In summary, this variant meets the criteria to be classified as pathogenic 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: PS3, PS4, PP4_Moderate, PP1, PM2_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16612528/MONDO:0008535/136

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENG NM_001114753.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 1.37
• Publications: 4 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

Specifications for ENG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.991G>A	p.Gly331Ser	missense splice_region	Exon 7 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.991G>A	p.Gly331Ser	missense splice_region	Exon 7 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.445G>A	p.Gly149Ser	missense splice_region	Exon 7 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.991G>A	p.Gly331Ser	missense splice_region	Exon 7 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.991G>A	p.Gly331Ser	missense splice_region	Exon 7 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.991G>A	p.Gly331Ser	missense splice_region	Exon 7 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00 AC: 0 AN: 203726 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000142 AC: 2 AN: 1404106 Hom.: 0 Cov.: 33 AF XY: 0.00000289 AC XY: 2 AN XY: 692252

African (AFR) AF: 0.00 AC: 0 AN: 31902

American (AMR) AF: 0.00 AC: 0 AN: 36844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22328

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.00 AC: 0 AN: 77080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5146

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1082774

Other (OTH) AF: 0.00 AC: 0 AN: 57846

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (7)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.40		Gain of disorder (P = 0.046)
MVP		0.73
MPC		0.48
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.64
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.030		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: rs1060501410; hg19: chr9-130587079; COSMIC: COSV61228053; COSMIC: COSV61228053;