15-58000438-T-C

Variant names:

• chr15-58000438-T-C
• rs6493973
• NM_003888.4:c.494-5299A>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.494-5299A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 151,886 control chromosomes in the GnomAD database, including 61,920 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 (61920 hom., cov: 31)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216
• Publications: 3 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=-1.0).
• 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.494-5299A>G		intron	N/A	NP_003879.2
	ALDH1A2	NM_001206897.2		c.431-5299A>G		intron	N/A	NP_001193826.1	O94788-3
	ALDH1A2	NM_170696.3		c.494-5299A>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.494-5299A>G		intron	N/A	ENSP00000249750.4	O94788-1
	ALDH1A2	ENST00000347587.7	TSL:1	c.494-5299A>G		intron	N/A	ENSP00000309623.3	O94788-2
	ALDH1A2	ENST00000559517.5	TSL:1	c.206-5299A>G		intron	N/A	ENSP00000453408.1	O94788-4

Frequencies

GnomAD3 genomes AF: 0.895 AC: 135886 AN: 151768 Hom.: 61895 Cov.: 31

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.947

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: 0.923

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

GnomAD4 genome AF: 0.895 AC: 135960 AN: 151886 Hom.: 61920 Cov.: 31 AF XY: 0.898 AC XY: 66699 AN XY: 74260

African (AFR) AF: 0.707 AC: 29264 AN: 41382

American (AMR) AF: 0.954 AC: 14538 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.947 AC: 3278 AN: 3460

East Asian (EAS) AF: 1.00 AC: 5153 AN: 5154

South Asian (SAS) AF: 0.984 AC: 4748 AN: 4824

European-Finnish (FIN) AF: 0.969 AC: 10283 AN: 10610

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

European-Non Finnish (NFE) AF: 0.966 AC: 65598 AN: 67900

Other (OTH) AF: 0.924 AC: 1945 AN: 2106

Alfa AF: 0.947 Hom.: 109431

Bravo AF: 0.885

Asia WGS AF: 0.975 AC: 3392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.66
PhyloP100		-0.22
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: rs6493973; hg19: chr15-58292636;