NM_001114753.3:c.1415_1424delAGAGCTTTGT

Variant names:

• chr9-127818719-CACAAAGCTCT-C
• rs1060501412
• NM_001114753.3:c.1415_1424delAGAGCTTTGT

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_001114753.3(ENG):c.1415_1424delAGAGCTTTGT (p.Gln472ArgfsTer16) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.30
• Publications: 0 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: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000225032 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 11 of 15) at amino acid 472 of 658, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~486 amino acids (172 amino acids lost).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ENG NM_001114753.3	MANE Select	c.1415_1424delAGAGCTTTGT p.Gln472ArgfsTer16	frameshift	Exon 11 of 15	Prot: NP_001108225.1 UniProt:
	ENG NM_000118.4		c.1415_1424delAGAGCTTTGT p.Gln472ArgfsTer16	frameshift	Exon 11 of 14	Prot: NP_000109.1 UniProt:
	ENG NM_001278138.2		c.869_878delAGAGCTTTGT p.Gln290ArgfsTer16	frameshift	Exon 11 of 15	Prot: NP_001265067.1 UniProt:

ENG NM_001114753.3

MANE Select

HGVSc / HGVSpc.1415_1424delAGAGCTTTGTp.Gln472ArgfsTer16

Exon rankExon 11 of 15

frameshift

Prot: NP_001108225.1UniProt: P17813-1

ENG NM_000118.4

HGVSc / HGVSpc.1415_1424delAGAGCTTTGTp.Gln472ArgfsTer16

Exon rankExon 11 of 14

frameshift

Prot: NP_000109.1UniProt: P17813-2

ENG NM_001278138.2

HGVSc / HGVSpc.869_878delAGAGCTTTGTp.Gln290ArgfsTer16

Exon rankExon 11 of 15

frameshift

Prot: NP_001265067.1UniProt: F5GX88

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ENG ENST00000373203.9	TSL:1MANE Select	c.1415_1424delAGAGCTTTGT p.Gln472ArgfsTer16	frameshift	Exon 11 of 15	Prot: ENSP00000362299.4 UniProt:
	ENG ENST00000344849.5	TSL:1	c.1415_1424delAGAGCTTTGT p.Gln472ArgfsTer16	frameshift	Exon 11 of 14	Prot: ENSP00000341917.3 UniProt:
	ENG ENST00000714047.1		c.1415_1424delAGAGCTTTGT p.Gln472ArgfsTer16	frameshift	Exon 11 of 15	Prot: ENSP00000519338.1 UniProt:

ENG ENST00000373203.9

TSL:1MANE Select

HGVSc / HGVSpc.1415_1424delAGAGCTTTGTp.Gln472ArgfsTer16

Exon rankExon 11 of 15

frameshift

Prot: ENSP00000362299.4UniProt: P17813-1

ENG ENST00000344849.5

TSL:1

HGVSc / HGVSpc.1415_1424delAGAGCTTTGTp.Gln472ArgfsTer16

Exon rankExon 11 of 14

frameshift

Prot: ENSP00000341917.3UniProt: P17813-2

ENG ENST00000714047.1

HGVSc / HGVSpc.1415_1424delAGAGCTTTGTp.Gln472ArgfsTer16

Exon rankExon 11 of 15

frameshift

Prot: ENSP00000519338.1UniProt: A0AAQ5BHC4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary hemorrhagic telangiectasia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	4.3

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1060501412;

hg19: chr9-130580998;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar