rs41358947

Positions:

• chr9-127816001-A-G

Variant summary

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

The ENST00000373203.9(ENG):​c.1794T>C​(p.Gly598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,610,468 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (110 hom.)
• Consequence: ENG ENST00000373203.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.01

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=-0.68).
• BP6: Variant 9-127816001-A-G is Benign according to our data. Variant chr9-127816001-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 213203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127816001-A-G is described in Lovd as [Benign]. Variant chr9-127816001-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2200/152302) while in subpopulation AFR AF= 0.0417 (1733/41554). AF 95% confidence interval is 0.0401. There are 44 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2200 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1794T>C	p.Gly598=	synonymous_variant	14/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1794T>C	p.Gly598=	synonymous_variant	14/14		NP_000109.1
ENG	NM_001278138.2	c.1248T>C	p.Gly416=	synonymous_variant	14/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1794T>C	p.Gly598=	synonymous_variant	14/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.1794T>C	p.Gly598=	synonymous_variant	14/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.1248T>C	p.Gly416=	synonymous_variant	14/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2200 AN: 152184 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00832 AC: 2019 AN: 242772 Hom.: 35 AF XY: 0.00885 AC XY: 1166 AN XY: 131712

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000388

Gnomad SAS exome AF: 0.0347

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00485 AC: 7066 AN: 1458166 Hom.: 110 Cov.: 31 AF XY: 0.00562 AC XY: 4072 AN XY: 725040

Gnomad4 AFR exome AF: 0.0448

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0341

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.0144 AC: 2200 AN: 152302 Hom.: 44 Cov.: 33 AF XY: 0.0146 AC XY: 1084 AN XY: 74488

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.00803

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0366

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00689 Hom.: 8

Bravo AF: 0.0162

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gly598Gly in exon 14A of ENG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 4.0% (178/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs41358947). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2014	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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2017

This alteration is classified as 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.3
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs41358947; hg19: chr9-130578280;