9-127843248-G-C

Position:

• chr9-127843248-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001114753.3(ENG):​c.68-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 30)
• Consequence: ENG NM_001114753.3 splice_region, intron
• Scores: Splicing: ADA: 0.9965
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.48

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127843248-G-C is Pathogenic according to our data. Variant chr9-127843248-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 568333.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.68-3C>G		splice_region_variant, intron_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.68-3C>G		splice_region_variant, intron_variant			NP_000109.1
ENG	NM_001278138.2	c.-479-3C>G		splice_region_variant, intron_variant			NP_001265067.1
ENG	NM_001406715.1	c.68-3C>G		splice_region_variant, intron_variant			NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.68-3C>G		splice_region_variant, intron_variant		1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.68-3C>G		splice_region_variant, intron_variant		1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-479-3C>G		splice_region_variant, intron_variant		2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in skipping of exon 2 (PMID: 25970827). ClinVar contains an entry for this variant (Variation ID: 568333). This variant has been observed in individuals with ENG-related disease (PMID: 25970827; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.75		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs773334730; hg19: chr9-130605527;