rs1554810373

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001114753.3(ENG):​c.673C>T​(p.Pro225Ser) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ENG
NM_001114753.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21380967).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ENGNM_001114753.3 linkc.673C>T p.Pro225Ser missense_variant 5/15 ENST00000373203.9 NP_001108225.1 P17813-1Q96CG0A0A024R878
ENGNM_000118.4 linkc.673C>T p.Pro225Ser missense_variant 5/14 NP_000109.1 P17813-2Q5T9B9
ENGNM_001278138.2 linkc.127C>T p.Pro43Ser missense_variant 5/15 NP_001265067.1 P17813Q96CG0F5GX88B7Z6Y5
ENGNM_001406715.1 linkc.673C>T p.Pro225Ser missense_variant 5/8 NP_001393644.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ENGENST00000373203.9 linkc.673C>T p.Pro225Ser missense_variant 5/151 NM_001114753.3 ENSP00000362299.4 P17813-1
ENGENST00000344849.4 linkc.673C>T p.Pro225Ser missense_variant 5/141 ENSP00000341917.3 P17813-2
ENGENST00000480266.6 linkc.127C>T p.Pro43Ser missense_variant 5/152 ENSP00000479015.1 F5GX88

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1435834
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
712304
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This sequence change is predicted to replace proline with serine at codon 225 of the ENG protein (p.(Pro225Ser)). The proline residue is moderately conserved with serine present in two mammals (100 vertebrates, UCSC), and is located in the C-terminal part of the OR1 domain. There is a moderate physicochemical difference between proline and serine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
T;T;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.69
T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;.;L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.5
N;.;N
REVEL
Benign
0.019
Sift
Benign
0.47
T;.;T
Sift4G
Benign
0.16
T;T;T
Polyphen
0.21
B;.;.
Vest4
0.26
MutPred
0.37
Gain of MoRF binding (P = 0.0854);.;Gain of MoRF binding (P = 0.0854);
MVP
0.48
MPC
0.29
ClinPred
0.34
T
GERP RS
3.5
Varity_R
0.10
gMVP
0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130587990; API