rs16930129

Variant names:

• chr9-127843106-C-T
• rs11545664
• NM_001114753.3:c.207G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001114753.3(ENG):​c.207G>A​(p.Leu69Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0976 in 1,613,932 control chromosomes in the GnomAD database, including 9,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.14 (1782 hom., cov: 31)
  • Exomes 𝑓: 0.094 (7269 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.15
• Publications: 26 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-127843106-C-T is Benign according to our data. Variant chr9-127843106-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

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.207G>A	p.Leu69Leu	synonymous	Exon 2 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001406715.1		c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 8	NP_001393644.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20675 AN: 152100 Hom.: 1781 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.0928 AC: 23319 AN: 251284 AF XY: 0.0900

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0631

Gnomad ASJ exome AF: 0.0961

Gnomad EAS exome AF: 0.0456

Gnomad FIN exome AF: 0.0690

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0936 AC: 136802 AN: 1461714 Hom.: 7269 Cov.: 33 AF XY: 0.0924 AC XY: 67212 AN XY: 727158

African (AFR) AF: 0.255 AC: 8537 AN: 33470

American (AMR) AF: 0.0661 AC: 2955 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2633 AN: 26132

East Asian (EAS) AF: 0.0451 AC: 1789 AN: 39700

South Asian (SAS) AF: 0.0528 AC: 4556 AN: 86248

European-Finnish (FIN) AF: 0.0721 AC: 3850 AN: 53386

Middle Eastern (MID) AF: 0.167 AC: 959 AN: 5744

European-Non Finnish (NFE) AF: 0.0949 AC: 105545 AN: 1111938

Other (OTH) AF: 0.0990 AC: 5978 AN: 60378

GnomAD4 genome AF: 0.136 AC: 20687 AN: 152218 Hom.: 1782 Cov.: 31 AF XY: 0.132 AC XY: 9808 AN XY: 74452

African (AFR) AF: 0.239 AC: 9905 AN: 41518

American (AMR) AF: 0.107 AC: 1635 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.0517 AC: 268 AN: 5184

South Asian (SAS) AF: 0.0476 AC: 230 AN: 4828

European-Finnish (FIN) AF: 0.0625 AC: 663 AN: 10614

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7000 AN: 67994

Other (OTH) AF: 0.131 AC: 276 AN: 2112

Alfa AF: 0.126 Hom.: 1432

Bravo AF: 0.143

Asia WGS AF: 0.0480 AC: 168 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11545664; hg19: chr9-130605385; COSMIC: COSV61229249; COSMIC: COSV61229249;