Genetic Variant ALDH1A2:n.1971C>G (chr15-57954604-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The ENST00000560312.5(ALDH1A2):n.1971C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 166,114 control chromosomes in the GnomAD database, including 11,833 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 0.37 ( 11007 hom., cov: 33)

Exomes 𝑓: 0.32 ( 826 hom. )

Consequence

ALDH1A2
ENST00000560312.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.93

Publications

38 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4 link	c.*593C>G	3_prime_UTR_variant	Exon 13 of 13	ENST00000249750.9	NP_003879.2	O94788-1
ALDH1A2	NM_001206897.2 link	c.*593C>G	3_prime_UTR_variant	Exon 14 of 14		NP_001193826.1	O94788-3
ALDH1A2	NM_170696.3 link	c.*593C>G	3_prime_UTR_variant	Exon 12 of 12		NP_733797.1	O94788-2
ALDH1A2	NM_170697.3 link	c.*593C>G	3_prime_UTR_variant	Exon 11 of 11		NP_733798.1	O94788-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9 link	c.*593C>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_003888.4	ENSP00000249750.4		O94788-1

Frequencies

GnomAD3 genomes

AF:

0.366

AC:

55559

AN:

151986

Hom.:

11009

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.326

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.463

Gnomad OTH

AF:

0.354

GnomAD4 exome

AF:

0.320

AC:

4480

AN:

14010

Hom.:

826

Cov.:

AF XY:

0.313

AC XY:

2316

AN XY:

7388

show subpopulations

African (AFR)

AF:

0.192

AC:

AN:

302

American (AMR)

AF:

0.266

AC:

779

AN:

2932

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

AN:

136

East Asian (EAS)

AF:

0.160

AC:

244

AN:

1524

South Asian (SAS)

AF:

0.169

AC:

310

AN:

1832

European-Finnish (FIN)

AF:

0.457

AC:

278

AN:

608

Middle Eastern (MID)

AF:

0.200

AC:

AN:

European-Non Finnish (NFE)

AF:

0.420

AC:

2590

AN:

6170

Other (OTH)

AF:

0.358

AC:

174

AN:

486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

133

267

400

534

667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.365

AC:

55565

AN:

152104

Hom.:

11007

Cov.:

AF XY:

0.361

AC XY:

26857

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.247

AC:

10235

AN:

41490

American (AMR)

AF:

0.302

AC:

4610

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

1130

AN:

3464

East Asian (EAS)

AF:

0.183

AC:

951

AN:

5190

South Asian (SAS)

AF:

0.172

AC:

830

AN:

4816

European-Finnish (FIN)

AF:

0.475

AC:

5015

AN:

10562

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.463

AC:

31452

AN:

67984

Other (OTH)

AF:

0.351

AC:

741

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1783

3567

5350

7134

8917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.414

Hom.:

7520

Bravo

AF:

0.349

Asia WGS

AF:

0.163

AC:

567

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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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15-57954604-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over