rs1554809516

Variant names:

• chr9-127819952-C-T
• rs1554809516
• NM_001114753.3:c.1220G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):​c.1220G>A​(p.Ser407Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.63
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000225032 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-127819952-C-T is Pathogenic according to our data. Variant chr9-127819952-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 458331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1220G>A	p.Ser407Asn	missense_variant	Exon 9 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1220G>A	p.Ser407Asn	missense_variant	Exon 9 of 14		NP_000109.1
ENG	NM_001278138.2	c.674G>A	p.Ser225Asn	missense_variant	Exon 9 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1568+1241C>T		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1220G>A	p.Ser407Asn	missense_variant	Exon 9 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Aug 08, 2024

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Jan 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies using activated monocytes isolated from a carrier individual indicate that this variant leads to a defect in the maturation of the ENG protein and its traffic to the cell membrane. However, transient over-expression experiments using HeLa cells in culture show that it does not interfere with protein transport into the cell membrane in that system (PMID: 22022569). The clinical relevance of these findings is uncertain. This variant has been reported in several individuals affected with hereditary hemorrhagic telangiectasia and to segregate with the disease in one family (PMID: 11440987, 16542389 , 16690726 , 22991266). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 407 of the ENG protein (p.Ser407Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.1	M;.;M
PhyloP100		2.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.97	D;.;.
Vest4		0.83
MutPred		0.86		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.88
MPC		0.76
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.97
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554809516; hg19: chr9-130582231;