NM_000693.4:c.172dupG
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000693.4(ALDH1A3):c.172dupG(p.Glu58GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000693.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH1A3 | NM_000693.4 | c.172dupG | p.Glu58GlyfsTer5 | frameshift_variant | Exon 2 of 13 | ENST00000329841.10 | NP_000684.2 | |
ALDH1A3 | NM_001293815.2 | c.172dupG | p.Glu58GlyfsTer5 | frameshift_variant | Exon 2 of 10 | NP_001280744.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461284Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726980
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Isolated microphthalmia 8 Pathogenic:1
This sequence change results in a frameshift variant (p.Glu58Glyfs*5) in the ALDH1A3 gene, leading to a premature stop codon shortly downstream. This is expected to result in either a truncated protein or nonsense-mediated mRNA decay. Loss-of-function variants in ALDH1A3 are an established mechanism of disease associated with autosomal recessive microphthalmia (OMIM #615113). This variant is extremely rare in population databases (gnomAD allele frequency: 0.0000006198). In silico prediction (MutationTaster: disease causing) supports a deleterious impact, although other predictors are unavailable. Based on ACMG criteria (PVS1, PP1, PP2), this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.