15-100880021-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000693.4(ALDH1A3):c.99+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,444,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.524

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-100880021-C-T is Benign according to our data. Variant chr15-100880021-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1675588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000329 (50/151824) while in subpopulation AMR AF= 0.000918 (14/15258). AF 95% confidence interval is 0.000554. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.99+15C>T		intron_variant		ENST00000329841.10
ALDH1A3	NM_001293815.2	c.99+15C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.99+15C>T		intron_variant		1	NM_000693.4	P1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151714 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000302 AC: 23 AN: 76260 Hom.: 0 AF XY: 0.000320 AC XY: 14 AN XY: 43724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.000954

GnomAD4 exome AF: 0.000178 AC: 230 AN: 1292988 Hom.: 0 Cov.: 29 AF XY: 0.000164 AC XY: 104 AN XY: 635788

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000729

Gnomad4 SAS exome AF: 0.0000291

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.000741

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151824 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74212

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000251

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000495

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 28, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

ALDH1A3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Benign	0.95

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

LitVar

Other links and lift over

dbSNP: rs749764506; hg19: chr15-101420226;