15-58001824-T-C

Variant names:

• chr15-58001824-T-C
• rs2218261
• NM_003888.4:c.494-6685A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003888.4(ALDH1A2):​c.494-6685A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 151,842 control chromosomes in the GnomAD database, including 62,498 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.90 (62498 hom., cov: 31)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 4 publications found

Genes affected

ALDH1A2 (HGNC:15472): (aldehyde dehydrogenase 1 family member A2) This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011]

ALDH1A2 Gene-Disease associations (from GenCC):

• diaphragmatic hernia 4, with cardiovascular defects

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003888.4. 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
	ALDH1A2	NM_003888.4	MANE Select	c.494-6685A>G		intron	N/A	NP_003879.2
	ALDH1A2	NM_001206897.2		c.431-6685A>G		intron	N/A	NP_001193826.1	O94788-3
	ALDH1A2	NM_170696.3		c.494-6685A>G		intron	N/A	NP_733797.1	O94788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.494-6685A>G		intron	N/A	ENSP00000249750.4	O94788-1
	ALDH1A2	ENST00000347587.7	TSL:1	c.494-6685A>G		intron	N/A	ENSP00000309623.3	O94788-2
	ALDH1A2	ENST00000559517.5	TSL:1	c.206-6685A>G		intron	N/A	ENSP00000453408.1	O94788-4

Frequencies

GnomAD3 genomes AF: 0.901 AC: 136696 AN: 151724 Hom.: 62467 Cov.: 31

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.955

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.966

Gnomad OTH AF: 0.928

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

GnomAD4 genome AF: 0.901 AC: 136782 AN: 151842 Hom.: 62498 Cov.: 31 AF XY: 0.903 AC XY: 67051 AN XY: 74222

African (AFR) AF: 0.727 AC: 30127 AN: 41418

American (AMR) AF: 0.955 AC: 14550 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3284 AN: 3464

East Asian (EAS) AF: 1.00 AC: 5144 AN: 5146

South Asian (SAS) AF: 0.984 AC: 4741 AN: 4818

European-Finnish (FIN) AF: 0.969 AC: 10285 AN: 10612

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.966 AC: 65543 AN: 67840

Other (OTH) AF: 0.928 AC: 1955 AN: 2106

Alfa AF: 0.944 Hom.: 197655

Bravo AF: 0.891

Asia WGS AF: 0.980 AC: 3407 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.073
DANN	Benign	0.39
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2218261; hg19: chr15-58294022;