rs368533266

Positions:

chr9-127818828-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS1_SupportingBP4BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1316A>C variant in ENG is a missense variant predicted to cause substitution of lysine by threonine at amino acid 439 (p.Lys439Thr). The filtering allele frequency (the lower threshold of the 95% CI of 15/10368) of the c.1316A>C variant in ENG is 0.0008918 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Additionally, functional assays showed the variant protein localized to the cell surface and had normal BMP9 response indicating that this variant does not impact protein function (BS3_Supporting; PMID:25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP4, BS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252800/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:2

Conservation

PhyloP100: 0.251

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ENG	NM_001114753.3 linkuse as main transcript	c.1316A>C	p.Lys439Thr	missense_variant	11/15	ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1 linkuse as main transcript	n.1568+117T>G		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4 linkuse as main transcript	c.1316A>C	p.Lys439Thr	missense_variant	11/14		NP_000109.1
ENG	NM_001278138.2 linkuse as main transcript	c.770A>C	p.Lys257Thr	missense_variant	11/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.1316A>C	p.Lys439Thr	missense_variant	11/15	1	NM_001114753.3	ENSP00000362299	P2	P17813-1
	ENST00000439298.5 linkuse as main transcript	n.1568+117T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251416

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000897

AC:

131

AN:

1459986

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726294

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:1Benign:1

Likely benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.1316A>C variant in ENG is a missense variant predicted to cause substitution of lysine by threonine at amino acid 439 (p.Lys439Thr). The filtering allele frequency (the lower threshold of the 95% CI of 15/10368) of the c.1316A>C variant in ENG is 0.0008918 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of less than or equal to 0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Additionally, functional assays showed the variant protein localized to the cell surface and had normal BMP9 response indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP4, BS3_Supporting (specification version 1.0.0; 1/4/2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2017

The c.1316A>C; p.Lys439Thr variant (rs368533266) was reported in a patient that carried a deletion in exon 6 of the ENG gene (Mallet, 2015). Functional studies by Mallet (2015) also showed that the p.Lys439Thr is properly targeted to the cell surface and stimulates ALK1 signaling in response to BMP9, features that are otherwise reduced in defective ENG polypeptides. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the Ashkenazi Jewish population (identified on 15 out of 9,850 chromosomes), and is reported to the ClinVar database (Variation ID: 365088). The lysine at position 439 is moderately conserved considering 12 species (Alamut v2.9.0) and computational analyses of the p.Lys439Thr variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on these observations, the p.Lys439Thr variant is likely to be benign. -

Hereditary hemorrhagic telangiectasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.9

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.041

Sift

Benign

0.085

T;.;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.023

B;.;.

Vest4

0.21

MVP

0.26

MPC

0.27

ClinPred

0.0049

GERP RS

0.63

Varity_R

0.23

gMVP

0.77

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