rs41522944

Positions:

• chr9-127843193-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001114753.3(ENG):​c.120C>T​(p.Gly40Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,614,206 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0052 (25 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.03

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-127843193-G-A is Benign according to our data. Variant chr9-127843193-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 237016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127843193-G-A is described in Lovd as [Likely_benign]. Variant chr9-127843193-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00341 (519/152330) while in subpopulation NFE AF= 0.00563 (383/68026). AF 95% confidence interval is 0.00516. There are 2 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 519 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.120C>T	p.Gly40Gly	synonymous_variant	2/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.120C>T	p.Gly40Gly	synonymous_variant	2/14		NP_000109.1
ENG	NM_001406715.1	c.120C>T	p.Gly40Gly	synonymous_variant	2/8		NP_001393644.1
ENG	NM_001278138.2	c.-427C>T		5_prime_UTR_variant	2/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.120C>T	p.Gly40Gly	synonymous_variant	2/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.120C>T	p.Gly40Gly	synonymous_variant	2/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-427C>T		5_prime_UTR_variant	2/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152212 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00322 AC: 809 AN: 251452 Hom.: 4 AF XY: 0.00318 AC XY: 432 AN XY: 135900

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00535

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00523 AC: 7645 AN: 1461876 Hom.: 25 Cov.: 32 AF XY: 0.00503 AC XY: 3661 AN XY: 727238

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00633

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152330 Hom.: 2 Cov.: 30 AF XY: 0.00298 AC XY: 222 AN XY: 74482

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00463 Hom.: 1

Bravo AF: 0.00353

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ENG: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gly40Gly in exon 2 of ENG: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.5% (44/8600) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs41522944). -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2014

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.3
DANN	Benign	0.86

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: rs41522944; hg19: chr9-130605472;