9-127824907-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001114753.3(ENG):c.884C>G(p.Thr295Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T295I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 28)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127824907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 571294.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.884C>G	p.Thr295Arg	missense_variant	7/15	ENST00000373203.9
ENG	NM_000118.4	c.884C>G	p.Thr295Arg	missense_variant	7/14
ENG	NM_001278138.2	c.338C>G	p.Thr113Arg	missense_variant	7/15
ENG	NM_001406715.1	c.884C>G	p.Thr295Arg	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.884C>G	p.Thr295Arg	missense_variant	7/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.884C>G	p.Thr295Arg	missense_variant	7/14	1		A2
ENG	ENST00000480266.6	c.338C>G	p.Thr113Arg	missense_variant	7/15	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.0	D;.;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.58		Loss of phosphorylation at T295 (P = 0.0266);.;Loss of phosphorylation at T295 (P = 0.0266);
MVP		0.66
MPC		0.85
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.62
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs12042; hg19: chr9-130587186;