9-127815922-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000118.4(ENG):c.1873C>G(p.Gln625Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000479 in 1,587,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ENG
NM_000118.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.69

Variant links:

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]

ENG links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04495424).

BP6

Variant 9-127815922-G-C is Benign according to our data. Variant chr9-127815922-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577031.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr9-127815922-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3 link	c.1852+21C>G		intron_variant	Intron 14 of 14	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 link	c.1873C>G	p.Gln625Glu	missense_variant	Exon 14 of 14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 link	c.1306+21C>G		intron_variant	Intron 14 of 14		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 link	n.-144G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENG	ENST00000344849.4 link	c.1873C>G	p.Gln625Glu	missense_variant	Exon 14 of 14	1		ENSP00000341917.3	P17813-2
ENG	ENST00000373203.9 link	c.1852+21C>G		intron_variant	Intron 14 of 14	1	NM_001114753.3	ENSP00000362299.4	P17813-1
ENG	ENST00000480266.6 link	c.1306+21C>G		intron_variant	Intron 14 of 14	2		ENSP00000479015.1	F5GX88
ENSG00000225032	ENST00000439298.5 link	n.-144G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

206126

Hom.:

AF XY:

0.0000270

AC XY:

AN XY:

111146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000779

Gnomad OTH exome

AF:

0.000193

GnomAD4 exome

AF:

0.0000439

AC:

AN:

1435240

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

711436

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000527

Gnomad4 OTH exome

AF:

0.0000842

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:1

Oct 14, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ENG variant (rs147188969) is rare (<0.1%) in a large population dataset (gnomAD: 10/237498 total alleles; 0.004211%; no homozygotes). A single submitter in ClinVar classifies this variant as uncertain and p.Gln625Glu has not been reported in the literature to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be benign. The glutamine residue at this position is evolutionarily conserved across some species, but not all. Due to lack of segregation and functional data, we consider the clinical significance of c.1873C>G to be uncertain at this time. -

not specified

Benign:1

Oct 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ENG c.1873C>G (p.Gln625Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 1587608 control chromosomes. The observed variant frequency is approximately 1.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in ENG causing Hereditary Hemorrhagic Telangiectasia phenotype (4.2e-05). To our knowledge, no occurrence of c.1873C>G in individuals affected with Hereditary Hemorrhagic Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 577031). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary hemorrhagic telangiectasia

Benign:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.28

M_CAP

Benign

0.0029

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.070

REVEL

Benign

0.058

Sift

Pathogenic

0.0

Sift4G

Benign

0.17

Vest4

0.29

MVP

0.44

ClinPred

0.36

GERP RS

4.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over