rs1060501408

Variant names:

• chr9-127854482-G-A
• rs1060501408
• NM_001114753.3:c.-127C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001114753.3(ENG):​c.-127C>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.70
• Publications: 11 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, Labcorp Genetics (formerly Invitae), G2P, 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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127854482-G-A is Pathogenic according to our data. Variant chr9-127854482-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 407113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33). . Strength limited to SUPPORTING due to the PP5.

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.-127C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001108225.1	P17813-1
	ENG	NM_001114753.3	MANE Select	c.-127C>T		5_prime_UTR	Exon 1 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.-127C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-127C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.-127C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.-127C>T		5_prime_UTR	Exon 1 of 15	ENSP00000362299.4	P17813-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 877902 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 441396

African (AFR) AF: 0.00 AC: 0 AN: 19704

American (AMR) AF: 0.00 AC: 0 AN: 24756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17404

East Asian (EAS) AF: 0.00 AC: 0 AN: 31948

South Asian (SAS) AF: 0.00 AC: 0 AN: 58082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3074

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 647632

Other (OTH) AF: 0.00 AC: 0 AN: 39820

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Hereditary hemorrhagic telangiectasia (3)
3	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.96
PhyloP100		2.7
PromoterAI		-0.13	Neutral
Mutation Taster		=62/238	disease causing (ClinVar)

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: rs1060501408; hg19: chr9-130616761;