9-127824342-C-T

Variant names:

• chr9-127824342-C-T
• rs1800956
• NM_001114753.3:c.1096G>A
• ENG p.Asp366Asn

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_001114753.3(ENG):​c.1096G>A​(p.Asp366Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D366G) has been classified as Likely benign. The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.23
• Publications: 31 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25109106).
• BP6: Variant 9-127824342-C-T is Benign according to our data. Variant chr9-127824342-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1356315.

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.1096G>A	p.Asp366Asn	missense	Exon 8 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1096G>A	p.Asp366Asn	missense	Exon 8 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.550G>A	p.Asp184Asn	missense	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.1096G>A	p.Asp366Asn	missense	Exon 8 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1096G>A	p.Asp366Asn	missense	Exon 8 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1096G>A	p.Asp366Asn	missense	Exon 8 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251480 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 14

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.011	D
Varity_R		0.18
gMVP		0.86
Mutation Taster		=82/18	polymorphism

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

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

Other links and lift over

dbSNP: rs1800956;

hg19: chr9-130586621;