chr9-127843069-C-A

Position:

• chr9-127843069-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.219+25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,582 control chromosomes in the GnomAD database, including 4,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (358 hom., cov: 31)
  • Exomes 𝑓: 0.069 (3823 hom.)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.521

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-127843069-C-A is Benign according to our data. Variant chr9-127843069-C-A is described in ClinVar as [Benign]. Clinvar id is 255144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.219+25G>T		intron_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.219+25G>T		intron_variant			NP_000109.1
ENG	NM_001278138.2	c.-328+25G>T		intron_variant			NP_001265067.1
ENG	NM_001406715.1	c.219+25G>T		intron_variant			NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.219+25G>T		intron_variant		1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.219+25G>T		intron_variant		1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-328+25G>T		intron_variant		2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9633 AN: 152200 Hom.: 355 Cov.: 31

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0962

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.0637

GnomAD3 exomes AF: 0.0640 AC: 16062 AN: 250950 Hom.: 681 AF XY: 0.0675 AC XY: 9161 AN XY: 135652

Gnomad AFR exome AF: 0.0641

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0955

Gnomad EAS exome AF: 0.00267

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0675

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0685 AC: 100153 AN: 1461264 Hom.: 3823 Cov.: 32 AF XY: 0.0701 AC XY: 50941 AN XY: 726948

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.0357

Gnomad4 ASJ exome AF: 0.0911

Gnomad4 EAS exome AF: 0.00458

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0550

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0694

GnomAD4 genome AF: 0.0633 AC: 9645 AN: 152318 Hom.: 358 Cov.: 31 AF XY: 0.0630 AC XY: 4690 AN XY: 74484

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0962

Gnomad4 EAS AF: 0.00385

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.0667

Gnomad4 OTH AF: 0.0626

Alfa AF: 0.0661 Hom.: 80

Bravo AF: 0.0619

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs7847860; hg19: chr9-130605348;