rs3739817

Positions:

• chr9-127824409-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001114753.3(ENG):​c.1029C>T​(p.Thr343Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,613,948 control chromosomes in the GnomAD database, including 6,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (440 hom., cov: 30)
  • Exomes 𝑓: 0.086 (6230 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.80

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=-0.53).
• BP6: Variant 9-127824409-G-A is Benign according to our data. Variant chr9-127824409-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127824409-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1029C>T	p.Thr343Thr	synonymous_variant	8/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1029C>T	p.Thr343Thr	synonymous_variant	8/14		NP_000109.1
ENG	NM_001278138.2	c.483C>T	p.Thr161Thr	synonymous_variant	8/15		NP_001265067.1
ENG	NM_001406715.1	c.1029C>T	p.Thr343Thr	synonymous_variant	8/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1029C>T	p.Thr343Thr	synonymous_variant	8/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1029C>T	p.Thr343Thr	synonymous_variant	8/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.483C>T	p.Thr161Thr	synonymous_variant	8/15	2		ENSP00000479015.1
ENG	ENST00000486329.1	n.-4C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10922 AN: 152016 Hom.: 439 Cov.: 30

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0832

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0680

GnomAD3 exomes AF: 0.0897 AC: 22536 AN: 251224 Hom.: 1257 AF XY: 0.0949 AC XY: 12898 AN XY: 135866

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.0889

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.0279

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.0882

Gnomad NFE exome AF: 0.0821

Gnomad OTH exome AF: 0.0778

GnomAD4 exome AF: 0.0863 AC: 126174 AN: 1461814 Hom.: 6230 Cov.: 36 AF XY: 0.0895 AC XY: 65118 AN XY: 727216

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.0870

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.0902

Gnomad4 NFE exome AF: 0.0820

Gnomad4 OTH exome AF: 0.0824

GnomAD4 genome AF: 0.0718 AC: 10917 AN: 152134 Hom.: 440 Cov.: 30 AF XY: 0.0742 AC XY: 5519 AN XY: 74358

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0676

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.0832

Gnomad4 NFE AF: 0.0808

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0783 Hom.: 786

Bravo AF: 0.0645

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.0770

EpiControl AF: 0.0729

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Thr343Thr in exon 8 of ENG: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 8.0% (691/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3739817). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2013	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	- -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:2

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	Nov 27, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3739817; hg19: chr9-130586688; COSMIC: COSV61227293; COSMIC: COSV61227293;