rs121918401

chr9-127819934-C-Achr9-127819934-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001114753.3(ENG):c.1238G>T(p.Gly413Val) variant causes a missense change. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G413D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.21

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 9-127819934-C-A is Pathogenic according to our data. Variant chr9-127819934-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16674.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-127819934-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1238G>T	p.Gly413Val	missense_variant	9/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1568+1223C>A		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1238G>T	p.Gly413Val	missense_variant	9/14
ENG	NM_001278138.2	c.692G>T	p.Gly231Val	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1238G>T	p.Gly413Val	missense_variant	9/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1568+1223C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.7	D;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.93		Loss of disorder (P = 0.0477);.;Loss of disorder (P = 0.0477);
MVP		0.97
MPC		0.89
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.73
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs121918401; hg19: chr9-130582213;