chr9-127824342-C-G

Variant names:

• chr9-127824342-C-G
• rs1800956
• NM_001114753.3:c.1096G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.1096G>C​(p.Asp366His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,613,884 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D366N) has been classified as Likely benign. The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0047 (35 hom., cov: 30)
  • Exomes 𝑓: 0.0039 (198 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• 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: 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 -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 11 uncertain in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020808578).
• BP6: Variant 9-127824342-C-G is Benign according to our data. Variant chr9-127824342-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0929 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.1096G>C	p.Asp366His	missense	Exon 8 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1096G>C	p.Asp366His	missense	Exon 8 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.550G>C	p.Asp184His	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>C	p.Asp366His	missense	Exon 8 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1096G>C	p.Asp366His	missense	Exon 8 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1096G>C	p.Asp366His	missense	Exon 8 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 717 AN: 151896 Hom.: 35 Cov.: 30

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00962

GnomAD2 exomes AF: 0.00919 AC: 2311 AN: 251480 AF XY: 0.00839

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00391 AC: 5723 AN: 1461870 Hom.: 198 Cov.: 33 AF XY: 0.00379 AC XY: 2755 AN XY: 727240

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26134

East Asian (EAS) AF: 0.0829 AC: 3293 AN: 39700

South Asian (SAS) AF: 0.00306 AC: 264 AN: 86252

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00126 AC: 1403 AN: 1112000

Other (OTH) AF: 0.00995 AC: 601 AN: 60396

GnomAD4 genome AF: 0.00470 AC: 715 AN: 152014 Hom.: 35 Cov.: 30 AF XY: 0.00502 AC XY: 373 AN XY: 74294

African (AFR) AF: 0.00118 AC: 49 AN: 41460

American (AMR) AF: 0.00216 AC: 33 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.100 AC: 514 AN: 5138

South Asian (SAS) AF: 0.00354 AC: 17 AN: 4808

European-Finnish (FIN) AF: 0.000756 AC: 8 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67990

Other (OTH) AF: 0.0105 AC: 22 AN: 2100

Alfa AF: 0.00423 Hom.: 14

Bravo AF: 0.00529

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00850 AC: 1032

Asia WGS AF: 0.0500 AC: 172 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Telangiectasia, hereditary hemorrhagic, type 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	ENG-related disorder (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.25
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.30
MVP		0.83
MPC		0.87
ClinPred		0.023	T
GERP RS		3.6
Varity_R		0.23
gMVP		0.92
Mutation Taster		=87/13	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: rs1800956; hg19: chr9-130586621; COSMIC: COSV100785221; COSMIC: COSV100785221;