9-127843094-C-T

Variant names:

• chr9-127843094-C-T
• rs755348996
• NM_001114753.3:c.219G>A
• ENG p.Thr73Thr

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PS3 PP5 BP4 BS2

The NM_001114753.3(ENG):​c.219G>A​(p.Thr73Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002562352: Published functional studies demonstrate that the c.219 G>A variant, which is part of the splice site consensus sequence in exon 2, leads to aberrant gene splicing and skipping of exon 2 (PMID:17384219)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T73T) has been classified as Uncertain significance. The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ENG NM_001114753.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9098
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 B:1
• Conservation: PhyloP100: -0.364
• Publications: 2 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for ENG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002562352: Published functional studies demonstrate that the c.219 G>A variant, which is part of the splice site consensus sequence in exon 2, leads to aberrant gene splicing and skipping of exon 2 (PMID: 17384219);; SCV002730727: mRNA studies showed exon 2 skipping (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65).
• PP5: Variant 9-127843094-C-T is Pathogenic according to our data. Variant chr9-127843094-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407128.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.219G>A	p.Thr73Thr	splice_region synonymous	Exon 2 of 15	NP_001108225.1	P17813-1
	ENG	NM_001278138.2		c.-328G>A		splice_region	Exon 2 of 15	NP_001265067.1	F5GX88
	ENG	NM_000118.4		c.219G>A	p.Thr73Thr	splice_region synonymous	Exon 2 of 14	NP_000109.1	Q5T9B9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.219G>A	p.Thr73Thr	splice_region synonymous	Exon 2 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.219G>A	p.Thr73Thr	splice_region synonymous	Exon 2 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000713957.1		c.-275G>A		splice_region	Exon 2 of 16	ENSP00000519250.1	A0AAQ5BH38

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251270 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	not provided (2)
2	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	ENG-related disorder (1)
1	-	-	Hereditary hemorrhagic telangiectasia (1)
1	-	-	not specified (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		-0.36
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs755348996;

hg19: chr9-130605373;