rs181330955

chr9-127815727-G-Achr9-127815727-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001114753.3(ENG):c.1932C>T(p.Ile644=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,559,734 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (117 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (511 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.724

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-127815727-G-A is Benign according to our data. Variant chr9-127815727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127815727-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.724 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1932C>T	p.Ile644=	synonymous_variant	15/15	ENST00000373203.9
ENG	NM_001278138.2	c.1386C>T	p.Ile462=	synonymous_variant	15/15
ENG	NM_000118.4	c.*190C>T		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1932C>T	p.Ile644=	synonymous_variant	15/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.*190C>T		3_prime_UTR_variant	14/14	1		A2
ENG	ENST00000480266.6	c.1386C>T	p.Ile462=	synonymous_variant	15/15	2

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1835 AN: 152226 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0281 AC: 4746 AN: 168698 Hom.: 385 AF XY: 0.0217 AC XY: 1977 AN XY: 91276

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.000834

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000827

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.00479 AC: 6745 AN: 1407390 Hom.: 511 Cov.: 31 AF XY: 0.00418 AC XY: 2911 AN XY: 696344

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00997

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000661

Gnomad4 OTH exome AF: 0.00770

GnomAD4 genome AF: 0.0122 AC: 1854 AN: 152344 Hom.: 117 Cov.: 33 AF XY: 0.0141 AC XY: 1049 AN XY: 74496

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0212

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.0204

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile644Ile in exon 15 of ENG: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 12.9% (17/132) of Mex ican chromosomes from a broad population by the 1000 Genomes Project (http://www .ncbi.nlm.nih.gov/projects/SNP; dbSNP rs181330955). -

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 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	-0.43
Cadd	Benign	10
Dann	Benign	0.90

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: rs181330955; hg19: chr9-130578006;