9-127824378-G-C

Variant names:

• chr9-127824378-G-C
• rs36092484
• NM_001114753.3:c.1060C>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.1060C>G​(p.Leu354Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L354L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21
• Publications: 7 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: 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=0.40899006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1060C>G	p.Leu354Val	missense_variant	Exon 8 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1060C>G	p.Leu354Val	missense_variant	Exon 8 of 14		NP_000109.1
ENG	NM_001278138.2	c.514C>G	p.Leu172Val	missense_variant	Exon 8 of 15		NP_001265067.1
ENG	NM_001406715.1	c.1060C>G	p.Leu354Val	missense_variant	Exon 8 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1060C>G	p.Leu354Val	missense_variant	Exon 8 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.3	M;.;M
PhyloP100		4.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.021	D;.;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.50
MutPred		0.30		Gain of sheet (P = 0.0166);.;Gain of sheet (P = 0.0166);
MVP		0.70
MPC		0.81
ClinPred		0.86	D
GERP RS		3.6
Varity_R		0.40
gMVP		0.68
Mutation Taster		=72/28	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: rs36092484; hg19: chr9-130586657;