rs864622781
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_002775.5(HTRA1):c.497G>A(p.Arg166His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
HTRA1
NM_002775.5 missense
NM_002775.5 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 9.86
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 Uncertain_significance. Variant got 1 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HTRA1 | NM_002775.5 | c.497G>A | p.Arg166His | missense_variant | 2/9 | ENST00000368984.8 | NP_002766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HTRA1 | ENST00000368984.8 | c.497G>A | p.Arg166His | missense_variant | 2/9 | 1 | NM_002775.5 | ENSP00000357980.3 | ||
HTRA1 | ENST00000648167.1 | c.179G>A | p.Arg60His | missense_variant | 2/9 | ENSP00000498033.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251496Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727202
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 17, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 166 of the HTRA1 protein (p.Arg166His). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 1910224). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HTRA1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg166 amino acid residue in HTRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25712943, 26063658, 28402226, 30447605, 31316458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D
REVEL
Pathogenic
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
1.0
.;D
Vest4
0.89
MutPred
0.56
.;Loss of catalytic residue at R166 (P = 0.0269);
MVP
0.98
MPC
1.6
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at