rs779149681
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_017613.4(DONSON):c.1047-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_017613.4 intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251390Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135860
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727144
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Microcephaly, short stature, and limb abnormalities Pathogenic:3
- -
Variant summary: DONSON c.1047-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publications report the variant to have an impact on splicing, specifically a reduction in DONSON transcript levels compared to normal controls as well as significantly increased retention of intron 6 (Reynolds_2017, Evrony_2017). The variant allele was found at a frequency of 4.8e-05 in 251390 control chromosomes. c.1047-9A>G has been reported in the literature in multiple individuals affected with Microcephaly, Short Stature, And Limb Abnormalities including several members of the same family in the homozygous state (Reynolds_2017, Evrony_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
Microcephaly-micromelia syndrome Pathogenic:2
- -
- -
not provided Pathogenic:2
This sequence change falls in intron 6 of the DONSON gene. It does not directly change the encoded amino acid sequence of the DONSON protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs779149681, gnomAD 0.01%). This variant has been observed in individuals with DONSON-related conditions (PMID: 28191891, 28630177). ClinVar contains an entry for this variant (Variation ID: 431414). Studies have shown that this variant alters DONSON gene expression (PMID: 28191891). Studies have shown that this variant results in retention of intron 6 and introduces a premature termination codon (PMID: 28630177). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 37644014, 34426522, 29760432, 31191207, 28191891, 32552793, 28630177, 34645488, Michel2024[CaseReport]) -
DONSON-related disorder Pathogenic:1
The DONSON c.1047-9A>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous and homozygous states in patients with microcephalic dwarfism or microcephaly micromelia syndrome, and segregates with the disease in affected family members (Reynolds et al. 2017. PubMed ID: 28191891; Evrony et al. 2017. PubMed ID: 28630177; Family 15DG2154 in Table S1, Maddirevula. 2020. PubMed ID: 32552793; Shamseldin et al. 2021. PubMed ID: 34645488). This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). In addition, RNA studies suggest that this variant causes intron 6 retention (Evrony et al. 2017. PubMed ID: 28630177). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at