2-74532713-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_013247.5(HTRA2):c.1210C>T(p.Arg404Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_013247.5 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HTRA2 | NM_013247.5 | c.1210C>T | p.Arg404Trp | missense_variant, splice_region_variant | 7/8 | ENST00000258080.8 | NP_037379.1 | |
LOXL3 | NM_032603.5 | c.*893G>A | 3_prime_UTR_variant | 14/14 | ENST00000264094.8 | NP_115992.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HTRA2 | ENST00000258080.8 | c.1210C>T | p.Arg404Trp | missense_variant, splice_region_variant | 7/8 | 1 | NM_013247.5 | ENSP00000258080.3 | ||
LOXL3 | ENST00000264094 | c.*893G>A | 3_prime_UTR_variant | 14/14 | 1 | NM_032603.5 | ENSP00000264094.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135912
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460688Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726700
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 404 of the HTRA2 protein (p.Arg404Trp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HTRA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 493282). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2022 | Reported in an adult male with early onset Parkinson disease in the published literature (Bogaerts et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17680806, 18790661, 24337630, 26965693, 20735469, 21701498, 19282869, 22675361, 25422467, 18401856) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2021 | The c.1210C>T (p.R404W) alteration is located in exon 7 (coding exon 7) of the HTRA2 gene. This alteration results from a C to T substitution at nucleotide position 1210, causing the arginine (R) at amino acid position 404 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at