rs4646580

Variant names:

• chr15-58037013-A-G
• rs4646580
• NM_003888.4:c.118-22732T>C

Variant summary

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

The NM_003888.4(ALDH1A2):​c.118-22732T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 151,372 control chromosomes in the GnomAD database, including 17,257 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 0.47 (17257 hom., cov: 31)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.118-22732T>C		intron_variant	Intron 1 of 12	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.54+20999T>C		intron_variant	Intron 2 of 13		NP_001193826.1
ALDH1A2	NM_170696.3	c.118-22732T>C		intron_variant	Intron 1 of 11		NP_733797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.118-22732T>C		intron_variant	Intron 1 of 12	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71216 AN: 151254 Hom.: 17249 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.452

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

GnomAD4 genome AF: 0.471 AC: 71255 AN: 151372 Hom.: 17257 Cov.: 31 AF XY: 0.467 AC XY: 34561 AN XY: 73938

African (AFR) AF: 0.409 AC: 16902 AN: 41344

American (AMR) AF: 0.404 AC: 6134 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1388 AN: 3456

East Asian (EAS) AF: 0.306 AC: 1572 AN: 5130

South Asian (SAS) AF: 0.273 AC: 1318 AN: 4820

European-Finnish (FIN) AF: 0.552 AC: 5822 AN: 10556

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36462 AN: 67574

Other (OTH) AF: 0.450 AC: 946 AN: 2104

Alfa AF: 0.505 Hom.: 9537

Bravo AF: 0.460

Asia WGS AF: 0.288 AC: 997 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.8
DANN	Benign	0.50
PhyloP100		0.082
PromoterAI		-0.013	Neutral
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: rs4646580; hg19: chr15-58329211;