Genetic Variant ALDH1A2:c.494-5299A>G (chr15-58000438-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.216

Publications

3 publications found

Variant links:

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)

ALDH1A2 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4 link	c.494-5299A>G	intron_variant	Intron 4 of 12	ENST00000249750.9	NP_003879.2	O94788-1
ALDH1A2	NM_001206897.2 link	c.431-5299A>G	intron_variant	Intron 5 of 13		NP_001193826.1	O94788-3
ALDH1A2	NM_170696.3 link	c.494-5299A>G	intron_variant	Intron 4 of 11		NP_733797.1	O94788-2
ALDH1A2	NM_170697.3 link	c.206-5299A>G	intron_variant	Intron 2 of 10		NP_733798.1	O94788-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9 link	c.494-5299A>G		intron_variant	Intron 4 of 12	1	NM_003888.4	ENSP00000249750.4		O94788-1

Frequencies

GnomAD3 genomes

AF:

0.895

AC:

135886

AN:

151768

Hom.:

61895

Cov.:

show subpopulations

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.:

AF XY:

0.898

AC XY:

66699

AN XY:

74260

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

611

1222

1834

2445

3056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.7

(source)

DANN

Benign

0.66

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over