chr15-100892597-GCAGGGTGGGCAGACAAAATC-G

Position:

• chr15-100892597-GCAGGGTGGGCAGACAAAATC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000693.4(ALDH1A3):​c.439_458del​(p.Trp147GlnfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH1A3 NM_000693.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.58

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]

ALDH1A3-AS1 (HGNC:55416): (ALDH1A3 antisense RNA 1)

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 15-100892597-GCAGGGTGGGCAGACAAAATC-G is Pathogenic according to our data. Variant chr15-100892597-GCAGGGTGGGCAGACAAAATC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1372977.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.439_458del	p.Trp147GlnfsTer7	frameshift_variant	4/13	ENST00000329841.10
ALDH1A3-AS1	NR_135827.1	n.3930_3949del		non_coding_transcript_exon_variant	2/2
ALDH1A3	NM_001293815.2	c.346-3330_346-3311del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.439_458del	p.Trp147GlnfsTer7	frameshift_variant	4/13	1	NM_000693.4	P1
ALDH1A3-AS1	ENST00000656756.1	n.4038_4057del		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with ALDH1A3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp147Glnfs*7) in the ALDH1A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH1A3 are known to be pathogenic (PMID: 23312594, 23591992, 24777706). -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr15-101432802;