9-127825770-C-G

Variant names:

• chr9-127825770-C-G
• rs751778614
• NM_001114753.3:c.614G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.614G>C​(p.Arg205Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.39
• 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127825770-C-G is Pathogenic according to our data. Variant chr9-127825770-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1751881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.614G>C	p.Arg205Pro	missense	Exon 5 of 15	NP_001108225.1
	ENG	NM_000118.4		c.614G>C	p.Arg205Pro	missense	Exon 5 of 14	NP_000109.1
	ENG	NM_001278138.2		c.68G>C	p.Arg23Pro	missense	Exon 5 of 15	NP_001265067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.614G>C	p.Arg205Pro	missense	Exon 5 of 15	ENSP00000362299.4
	ENG	ENST00000344849.5	TSL:1	c.614G>C	p.Arg205Pro	missense	Exon 5 of 14	ENSP00000341917.3
	ENG	ENST00000714047.1		c.614G>C	p.Arg205Pro	missense	Exon 5 of 15	ENSP00000519338.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.068	T
Sift4G	Benign	0.092	T
Polyphen		0.56	P
Vest4		0.62
MutPred		0.40		Loss of catalytic residue at R205 (P = 0.0028)
MVP		0.62
MPC		0.71
ClinPred		0.29	T
GERP RS		-2.2
Varity_R		0.66
gMVP		0.81
Mutation Taster		=56/44	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

Other links and lift over

dbSNP: rs751778614; hg19: chr9-130588049;