15-100893961-TC-T

Position:

• chr15-100893961-TC-T

Variant summary

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

The NM_000693.4(ALDH1A3):​c.550del​(p.Leu184CysfsTer2) variant causes a frameshift change involving the alteration of a non-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: 0.384

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 15-100893961-TC-T is Pathogenic according to our data. Variant chr15-100893961-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1801374.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.550del	p.Leu184CysfsTer2	frameshift_variant	6/13	ENST00000329841.10
ALDH1A3-AS1	NR_135827.1	n.2585del		non_coding_transcript_exon_variant	2/2
ALDH1A3	NM_001293815.2	c.346-1967del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.550del	p.Leu184CysfsTer2	frameshift_variant	6/13	1	NM_000693.4	P1
ALDH1A3-AS1	ENST00000656756.1	n.2693del		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr15-101434166;