15-100914711-GCT-ACA

Variant names:

• chr15-100914711-GCT-ACA
• NM_000693.4:c.1477_1479delGCTinsACA
• ALDH1A3 p.Ala493Thr

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP2 PP3

The NM_000693.4(ALDH1A3):​c.1477_1479delGCTinsACA​(p.Ala493Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A493P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.61
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-100914711-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 40204.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.2359 (below the threshold of 3.09). Trascript score misZ: 2.2507 (below the threshold of 3.09). GenCC associations: The gene is linked to isolated anophthalmia-microphthalmia syndrome, isolated microphthalmia 8.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	NM_000693.4	MANE Select	c.1477_1479delGCTinsACA	p.Ala493Thr	missense	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.1156_1158delGCTinsACA	p.Ala386Thr	missense	N/A	NP_001280744.1	H0Y2X5
	ALDH1A3-AS1	NR_135828.1		n.1748_1750delAGCinsTGT		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.1477_1479delGCTinsACA	p.Ala493Thr	missense	N/A	ENSP00000332256.5	P47895
	ALDH1A3	ENST00000346623.6	TSL:1	c.1156_1158delGCTinsACA	p.Ala386Thr	missense	N/A	ENSP00000343294.6	H0Y2X5
	ALDH1A3-AS1	ENST00000560068.2	TSL:1	n.1758_1760delAGCinsTGT		non_coding_transcript_exon	Exon 2 of 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-101454916;