Genetic Variant ALDH1A2:c.-6G>A (chr15-58065656-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003888.4(ALDH1A2):c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,579,938 control chromosomes in the GnomAD database, including 1,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.030 ( 105 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1323 hom. )

Consequence

ALDH1A2
NM_003888.4 5_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.557

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 links:

ALDH1A2-AS1 (HGNC:27515): (ALDH1A2 antisense RNA 1)

ALDH1A2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 15-58065656-C-T is Benign according to our data. Variant chr15-58065656-C-T is described in ClinVar as [Benign]. Clinvar id is 3060978.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-58065656-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0304 (4621/152124) while in subpopulation NFE AF= 0.0444 (3018/67954). AF 95% confidence interval is 0.0431. There are 105 homozygotes in gnomad4. There are 2215 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4 link	c.-6G>A	5_prime_UTR_variant	Exon 1 of 13	ENST00000249750.9	NP_003879.2	O94788-1
ALDH1A2	NM_001206897.2 link	c.-166G>A	5_prime_UTR_variant	Exon 1 of 14		NP_001193826.1	O94788-3
ALDH1A2	NM_170696.3 link	c.-6G>A	5_prime_UTR_variant	Exon 1 of 12		NP_733797.1	O94788-2
ALDH1A2-AS1	NR_147215.1 link	n.432C>T	non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9 link	c.-6G>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_003888.4	ENSP00000249750.4		O94788-1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4621

AN:

152006

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00785

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0717

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0444

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0336

AC:

6763

AN:

201018

Hom.:

151

AF XY:

0.0340

AC XY:

3695

AN XY:

108816

show subpopulations

Gnomad AFR exome

AF:

0.00774

Gnomad AMR exome

AF:

0.0244

Gnomad ASJ exome

AF:

0.0693

Gnomad EAS exome

AF:

0.000127

Gnomad SAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0468

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0411

AC:

58665

AN:

1427814

Hom.:

1323

Cov.:

AF XY:

0.0404

AC XY:

28563

AN XY:

707292

show subpopulations

Gnomad4 AFR exome

AF:

0.00646

Gnomad4 AMR exome

AF:

0.0246

Gnomad4 ASJ exome

AF:

0.0656

Gnomad4 EAS exome

AF:

0.000129

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.0478

Gnomad4 NFE exome

AF:

0.0458

Gnomad4 OTH exome

AF:

0.0378

GnomAD4 genome

AF:

0.0304

AC:

4621

AN:

152124

Hom.:

105

Cov.:

AF XY:

0.0298

AC XY:

2215

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00783

Gnomad4 AMR

AF:

0.0309

Gnomad4 ASJ

AF:

0.0717

Gnomad4 EAS

AF:

0.000390

Gnomad4 SAS

AF:

0.00851

Gnomad4 FIN

AF:

0.0405

Gnomad4 NFE

AF:

0.0444

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.0301

Hom.:

Bravo

AF:

0.0292

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ALDH1A2-related disorder

Benign:1

May 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over