rs587776445
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_002775.5(HTRA1):c.821G>A(p.Arg274Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,500 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002775.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HTRA1 | NM_002775.5 | c.821G>A | p.Arg274Gln | missense_variant | 4/9 | ENST00000368984.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HTRA1 | ENST00000368984.8 | c.821G>A | p.Arg274Gln | missense_variant | 4/9 | 1 | NM_002775.5 | P1 | |
HTRA1 | ENST00000648167.1 | c.503G>A | p.Arg168Gln | missense_variant | 4/9 | ||||
HTRA1 | ENST00000420892.1 | c.44G>A | p.Arg15Gln | missense_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250866Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135656
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461350Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727010
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 274 of the HTRA1 protein (p.Arg274Gln). This variant is present in population databases (rs587776445, gnomAD 0.002%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects HTRA1 function (PMID: 21482952, 25506911, 27164673, 31316458). 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 not expected to disrupt HTRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 156099). This missense change has been observed in individual(s) with CARASIL (PMID: 21482952). It has also been observed to segregate with disease in related individuals. - |
CARASIL syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at