rs1554950703
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_002775.5(HTRA1):c.614C>G(p.Ser205Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
HTRA1
NM_002775.5 missense
NM_002775.5 missense
Scores
11
1
1
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 20 pathogenic changes around while only 3 benign (87%) in NM_002775.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
?
Variant 10-122489463-C-G is Pathogenic according to our data. Variant chr10-122489463-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 560164.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HTRA1 | NM_002775.5 | c.614C>G | p.Ser205Cys | missense_variant | 3/9 | ENST00000368984.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HTRA1 | ENST00000368984.8 | c.614C>G | p.Ser205Cys | missense_variant | 3/9 | 1 | NM_002775.5 | P1 | |
HTRA1 | ENST00000648167.1 | c.296C>G | p.Ser99Cys | missense_variant | 3/9 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
CARASIL syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;in vitro | Department of Clinical Laboratory, Peking University People's Hospital | Apr 18, 2018 | Cerebral autosomal recessive arterial disease with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare inherited cerebral artery disease, which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis. It has been established that the high temperature requirement serine peptidase A1 (HTRA1) gene is a causative agent of CARASIL and represses signaling pathway transforming growth factor β1 (TGF-β1)/Smads. To date, 4 missense mutations and 2 nonsense mutations had been reported and they were distributed in exon3, 4 and 6 where located the HTRA1 protease domain, which might lead to the change of HTRA1 gene activity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
Polyphen
1.0
.;D
Vest4
0.93
MutPred
0.78
.;Loss of glycosylation at S205 (P = 0.0046);
MVP
0.99
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at