rs35400405

Positions:

• chr9-127854342-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.14C>T​(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,593,366 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.043 (259 hom., cov: 32)
  • Exomes 𝑓: 0.020 (494 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.282

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018308163).
• BP6: Variant 9-127854342-G-A is Benign according to our data. Variant chr9-127854342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127854342-G-A is described in Lovd as [Benign]. Variant chr9-127854342-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.14C>T	p.Thr5Met	missense_variant	1/15	ENST00000373203.9
ENG	NM_000118.4	c.14C>T	p.Thr5Met	missense_variant	1/14
ENG	NM_001406715.1	c.14C>T	p.Thr5Met	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.14C>T	p.Thr5Met	missense_variant	1/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.14C>T	p.Thr5Met	missense_variant	1/14	1		A2

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6610 AN: 152188 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0215 AC: 4471 AN: 207920 Hom.: 97 AF XY: 0.0192 AC XY: 2166 AN XY: 112672

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00721

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0204 AC: 29394 AN: 1441060 Hom.: 494 Cov.: 31 AF XY: 0.0197 AC XY: 14060 AN XY: 715048

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00699

Gnomad4 FIN exome AF: 0.00559

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0435 AC: 6621 AN: 152306 Hom.: 259 Cov.: 32 AF XY: 0.0410 AC XY: 3057 AN XY: 74482

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0356

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0269 Hom.: 103

Bravo AF: 0.0489

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.101 AC: 445

ESP6500EA AF: 0.0229 AC: 196

ExAC AF: 0.0216 AC: 2596

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2014	Thr5Met in exon 1 of ENG: This variant is not expected to have clinical signific ance because it has been identified in 10% (445/4390) of African American chromo somes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs35400405). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 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. -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.75
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.0030
Sift	Benign	0.15	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0020	B;.
Vest4		0.019
MPC		0.22
ClinPred		0.00060	T
GERP RS		0.097
Varity_R		0.014
gMVP		0.48

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: rs35400405; hg19: chr9-130616621;