rs4646561

Variant names:

• chr15-58061312-T-C
• rs4646561
• NM_003888.4:c.117+4222A>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.117+4222A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 151,880 control chromosomes in the GnomAD database, including 342 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 0.064 (342 hom., cov: 30)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• 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: 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.117+4222A>G		intron_variant	Intron 1 of 12	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.-43-3204A>G		intron_variant	Intron 1 of 13		NP_001193826.1
ALDH1A2	NM_170696.3	c.117+4222A>G		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.117+4222A>G		intron_variant	Intron 1 of 12	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9705 AN: 151766 Hom.: 341 Cov.: 30

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.0615

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0682

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

GnomAD4 genome AF: 0.0639 AC: 9703 AN: 151880 Hom.: 342 Cov.: 30 AF XY: 0.0656 AC XY: 4871 AN XY: 74218

African (AFR) AF: 0.0314 AC: 1300 AN: 41464

American (AMR) AF: 0.0761 AC: 1162 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0615 AC: 213 AN: 3464

East Asian (EAS) AF: 0.123 AC: 634 AN: 5170

South Asian (SAS) AF: 0.0872 AC: 420 AN: 4816

European-Finnish (FIN) AF: 0.0800 AC: 840 AN: 10496

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0724 AC: 4914 AN: 67900

Other (OTH) AF: 0.0680 AC: 143 AN: 2104

Alfa AF: 0.0591 Hom.: 50

Bravo AF: 0.0625

Asia WGS AF: 0.0930 AC: 322 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.41
DANN	Benign	0.47
PhyloP100		-1.2
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: rs4646561; hg19: chr15-58353510;