9-127825711-G-C

Variant names:

• chr9-127825711-G-C
• rs1554810373
• NM_001114753.3:c.673C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114753.3(ENG):​c.673C>G​(p.Pro225Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,834 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• 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: 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3219574).

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.673C>G	p.Pro225Ala	missense	Exon 5 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.673C>G	p.Pro225Ala	missense	Exon 5 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.127C>G	p.Pro43Ala	missense	Exon 5 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.673C>G	p.Pro225Ala	missense	Exon 5 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.673C>G	p.Pro225Ala	missense	Exon 5 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.673C>G	p.Pro225Ala	missense	Exon 5 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435834 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 712304

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 39100

South Asian (SAS) AF: 0.00 AC: 0 AN: 83856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4186

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102330

Other (OTH) AF: 0.00 AC: 0 AN: 59226

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.081
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.041
Sift	Benign	0.046	D
Sift4G	Benign	0.099	T
Polyphen		0.91	P
Vest4		0.40
MutPred		0.48		Gain of catalytic residue at P225 (P = 0.0146)
MVP		0.54
MPC		0.52
ClinPred		0.51	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.49
Mutation Taster		=79/21	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: rs1554810373; hg19: chr9-130587990;