rs3825924

Variant names:

• chr15-100905695-G-A
• rs3825924
• NM_000693.4:c.1233+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000693.4(ALDH1A3):​c.1233+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,551,604 control chromosomes in the GnomAD database, including 31,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2811 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28952 hom.)
• Consequence: ALDH1A3 NM_000693.4 splice_region, intron
• Scores: Splicing: ADA: 0.001339
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.559
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-100905695-G-A is Benign according to our data. Variant chr15-100905695-G-A is described in ClinVar as Benign. ClinVar VariationId is 256761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

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.1233+8G>A		splice_region intron	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.912+8G>A		splice_region intron	N/A	NP_001280744.1	H0Y2X5
	ALDH1A3-AS1	NR_135827.1		n.481-9629C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.1233+8G>A		splice_region intron	N/A	ENSP00000332256.5	P47895
	ALDH1A3	ENST00000346623.6	TSL:1	c.912+8G>A		splice_region intron	N/A	ENSP00000343294.6	H0Y2X5
	ALDH1A3	ENST00000856095.1		c.1332+8G>A		splice_region intron	N/A	ENSP00000526154.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25836 AN: 152002 Hom.: 2810 Cov.: 32

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.0815

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.222 AC: 44268 AN: 199200 AF XY: 0.216

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.542

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.193 AC: 270082 AN: 1399484 Hom.: 28952 Cov.: 32 AF XY: 0.192 AC XY: 132495 AN XY: 689742

African (AFR) AF: 0.0730 AC: 2263 AN: 31016

American (AMR) AF: 0.272 AC: 10205 AN: 37468

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 4416 AN: 22412

East Asian (EAS) AF: 0.526 AC: 20031 AN: 38078

South Asian (SAS) AF: 0.169 AC: 12848 AN: 76110

European-Finnish (FIN) AF: 0.201 AC: 10350 AN: 51396

Middle Eastern (MID) AF: 0.158 AC: 758 AN: 4804

European-Non Finnish (NFE) AF: 0.183 AC: 197594 AN: 1080594

Other (OTH) AF: 0.202 AC: 11617 AN: 57606

GnomAD4 genome AF: 0.170 AC: 25853 AN: 152120 Hom.: 2811 Cov.: 32 AF XY: 0.174 AC XY: 12914 AN XY: 74364

African (AFR) AF: 0.0759 AC: 3152 AN: 41530

American (AMR) AF: 0.227 AC: 3467 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3468

East Asian (EAS) AF: 0.518 AC: 2679 AN: 5170

South Asian (SAS) AF: 0.168 AC: 807 AN: 4812

European-Finnish (FIN) AF: 0.197 AC: 2078 AN: 10566

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12544 AN: 67984

Other (OTH) AF: 0.168 AC: 353 AN: 2106

Alfa AF: 0.178 Hom.: 4813

Bravo AF: 0.171

Asia WGS AF: 0.321 AC: 1114 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Isolated microphthalmia 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.51
DANN	Benign	0.74
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.030
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

Other links and lift over

dbSNP: rs3825924; hg19: chr15-101445900; COSMIC: COSV60901568;