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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.1220G>A	p.Ser407Asn	missense	Exon 9 of 15	NP_001108225.1
	ENG	NM_000118.4		c.1220G>A	p.Ser407Asn	missense	Exon 9 of 14	NP_000109.1
	ENG	NM_001278138.2		c.674G>A	p.Ser225Asn	missense	Exon 9 of 15	NP_001265067.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.1220G>A	p.Ser407Asn	missense	Exon 9 of 15	ENSP00000362299.4
	ENG	ENST00000344849.5	TSL:1	c.1220G>A	p.Ser407Asn	missense	Exon 9 of 14	ENSP00000341917.3
	ENG	ENST00000714047.1		c.1220G>A	p.Ser407Asn	missense	Exon 9 of 15	ENSP00000519338.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary hemorrhagic telangiectasia (1)
1	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.97	D
Vest4		0.83
MutPred		0.86		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;