rs762281569
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_024570.4(RNASEH2B):c.127C>T(p.Pro43Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,595,604 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P43H) has been classified as Uncertain significance.
Frequency
Consequence
NM_024570.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RNASEH2B | NM_024570.4 | c.127C>T | p.Pro43Ser | missense_variant | 2/11 | ENST00000336617.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RNASEH2B | ENST00000336617.8 | c.127C>T | p.Pro43Ser | missense_variant | 2/11 | 1 | NM_024570.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251300Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135834
GnomAD4 exome AF: 0.00000485 AC: 7AN: 1443560Hom.: 0 Cov.: 26 AF XY: 0.00000695 AC XY: 5AN XY: 719380
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74242
ClinVar
Submissions by phenotype
Aicardi-Goutieres syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 43 of the RNASEH2B protein (p.Pro43Ser). This variant is present in population databases (rs762281569, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RNASEH2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 312329). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at