NM_000693.4:c.172dupG

Variant names:

• chr15-100885336-C-CG
• NM_000693.4:c.172dupG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALDH1A3 NM_000693.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.82

Genes affected

ALDH1A3 (HGNC:409): (aldehyde dehydrogenase 1 family member A3) This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ENSG00000272639 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-100885336-C-CG is Pathogenic according to our data. Variant chr15-100885336-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3777064.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.172dupG	p.Glu58GlyfsTer5	frameshift_variant	Exon 2 of 13	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461284 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 8 Pathogenic:1

-

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-101425541;