rs36092484

Variant names:

• chr9-127824378-G-A
• rs36092484
• NM_001114753.3:c.1060C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-127824378-G-A
• chr9-127824378-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.1060C>T​(p.Leu354Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0149 in 1,614,118 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (181 hom., cov: 30)
  • Exomes 𝑓: 0.013 (299 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.21
• Publications: 7 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-127824378-G-A is Benign according to our data. Variant chr9-127824378-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 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.1060C>T	p.Leu354Leu	synonymous	Exon 8 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1060C>T	p.Leu354Leu	synonymous	Exon 8 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.514C>T	p.Leu172Leu	synonymous	Exon 8 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.1060C>T	p.Leu354Leu	synonymous	Exon 8 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1060C>T	p.Leu354Leu	synonymous	Exon 8 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1060C>T	p.Leu354Leu	synonymous	Exon 8 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5084 AN: 152110 Hom.: 180 Cov.: 30

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.0161 AC: 4056 AN: 251414 AF XY: 0.0144

Gnomad AFR exome AF: 0.0929

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0129 AC: 18907 AN: 1461890 Hom.: 299 Cov.: 33 AF XY: 0.0124 AC XY: 8993 AN XY: 727246

African (AFR) AF: 0.102 AC: 3418 AN: 33480

American (AMR) AF: 0.00715 AC: 320 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00365 AC: 315 AN: 86258

European-Finnish (FIN) AF: 0.0308 AC: 1645 AN: 53418

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.0110 AC: 12208 AN: 1112010

Other (OTH) AF: 0.0141 AC: 852 AN: 60396

GnomAD4 genome AF: 0.0334 AC: 5092 AN: 152228 Hom.: 181 Cov.: 30 AF XY: 0.0333 AC XY: 2478 AN XY: 74452

African (AFR) AF: 0.0889 AC: 3693 AN: 41522

American (AMR) AF: 0.0146 AC: 224 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.0310 AC: 329 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 753 AN: 68006

Other (OTH) AF: 0.0232 AC: 49 AN: 2108

Alfa AF: 0.0189 Hom.: 110

Bravo AF: 0.0360

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00830

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.57
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		4.2
Mutation Taster		=99/1	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: rs36092484; hg19: chr9-130586657;