rs993687029
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000303071.10(DONSON):c.1282C>T(p.Gln428Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,024 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000303071.10 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DONSON | NM_017613.4 | c.1282C>T | p.Gln428Ter | stop_gained | 8/10 | ENST00000303071.10 | NP_060083.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DONSON | ENST00000303071.10 | c.1282C>T | p.Gln428Ter | stop_gained | 8/10 | 1 | NM_017613.4 | ENSP00000307143 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251468Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2022 | The c.1282C>T (p.Q428*) alteration, located in exon 8 (coding exon 8) of the DONSON gene, consists of a C to T substitution at nucleotide position 1282. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 428. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (5/282858) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This mutation has been reported in the compound heterozygous state in individuals with DONSON-related microcephalic dwarfism (Reynolds, 2017). Functional studies found that cells containing this mutation expressed less protein when compared to wild-type (Reynolds, 2017). Based on the available evidence, this alteration is classified as pathogenic. - |
Microcephaly-micromelia syndrome;C4539873:Microcephaly, short stature, and limb abnormalities Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 12, 2021 | - - |
Microcephaly, short stature, and limb abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 05, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at