rs1554810272

Positions:

• chr9-127825358-C-G
• chr9-127825358-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.690-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: ENG NM_001114753.3 splice_acceptor
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.18

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.5, offset of -28, new splice context is: gcctggcctgtccgcttcAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127825358-C-G is Pathogenic according to our data. Variant chr9-127825358-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1075363.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-127825358-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.690-1G>C		splice_acceptor_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.690-1G>C		splice_acceptor_variant			NP_000109.1
ENG	NM_001278138.2	c.144-1G>C		splice_acceptor_variant			NP_001265067.1
ENG	NM_001406715.1	c.690-1G>C		splice_acceptor_variant			NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.690-1G>C		splice_acceptor_variant		1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.690-1G>C		splice_acceptor_variant		1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.144-1G>C		splice_acceptor_variant		2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1075363). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 10625079, 16525724, 22991266). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 of the ENG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	33
DANN	Benign	0.91
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: 27
DS_AL_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130587637;