rs1329127701

chr9-127824304-C-Gchr9-127824304-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001114753.3(ENG):c.1134G>C(p.Ala378=) variant causes a splice region, synonymous 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 (★). Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-127824304-C-G is Pathogenic according to our data. Variant chr9-127824304-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1074391.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.1134G>C	p.Ala378=	splice_region_variant, synonymous_variant	8/15	ENST00000373203.9
ENG	NM_000118.4	c.1134G>C	p.Ala378=	splice_region_variant, synonymous_variant	8/14
ENG	NM_001278138.2	c.588G>C	p.Ala196=	splice_region_variant, synonymous_variant	8/15
ENG	NM_001406715.1	c.1134G>C	p.Ala378=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1134G>C	p.Ala378=	splice_region_variant, synonymous_variant	8/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.1134G>C	p.Ala378=	splice_region_variant, synonymous_variant	8/14	1		A2
ENG	ENST00000480266.6	c.588G>C	p.Ala196=	splice_region_variant, synonymous_variant	8/15	2
ENG	ENST00000486329.1	n.102G>C		splice_region_variant, non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

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

Invitae

Nov 06, 2020

For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677, 15517393, 21158752; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 378 of the ENG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ENG protein. This variant also falls at the last nucleotide of exon 8 of the ENG coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	24
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 24
DS_DL_spliceai		0.68		Position offset: 0

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: chr9-130586583;