Genetic Variant NM_003888.4:c.-6G>A (chr15-58065656-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

8 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 links:

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

ALDH1A2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 3060978.Status of the report is no_assertion_criteria_provided, 0 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 105 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003888.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ALDH1A2	NM_003888.4	MANE Select	c.-6G>A	5_prime_UTR	Exon 1 of 13	NP_003879.2
ALDH1A2-AS1	NR_147215.1		n.432C>T	non_coding_transcript_exon	Exon 1 of 3
ALDH1A2	NM_001206897.2		c.-166G>A	5_prime_UTR	Exon 1 of 14	NP_001193826.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.-6G>A	5_prime_UTR	Exon 1 of 13	ENSP00000249750.4
ALDH1A2	ENST00000347587.7	TSL:1	c.-6G>A	5_prime_UTR	Exon 1 of 12	ENSP00000309623.3
ALDH1A2	ENST00000430119.6	TSL:2	n.-6G>A	non_coding_transcript_exon	Exon 1 of 14	ENSP00000416754.2

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

GnomAD2 exomes

AF:

0.0336

AC:

6763

AN:

201018

AF XY:

0.0340

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 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

African (AFR)

AF:

0.00646

AC:

211

AN:

32678

American (AMR)

AF:

0.0246

AC:

1014

AN:

41214

Ashkenazi Jewish (ASJ)

AF:

0.0656

AC:

1590

AN:

24236

East Asian (EAS)

AF:

0.000129

AC:

AN:

38838

South Asian (SAS)

AF:

0.0119

AC:

971

AN:

81650

European-Finnish (FIN)

AF:

0.0478

AC:

2459

AN:

51394

Middle Eastern (MID)

AF:

0.0245

AC:

138

AN:

5626

European-Non Finnish (NFE)

AF:

0.0458

AC:

50058

AN:

1093450

Other (OTH)

AF:

0.0378

AC:

2219

AN:

58728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

2902

5804

8706

11608

14510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1892

3784

5676

7568

9460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0304

AC:

4621

AN:

152124

Hom.:

105

Cov.:

AF XY:

0.0298

AC XY:

2215

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00783

AC:

325

AN:

41532

American (AMR)

AF:

0.0309

AC:

473

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0717

AC:

249

AN:

3472

East Asian (EAS)

AF:

0.000390

AC:

AN:

5126

South Asian (SAS)

AF:

0.00851

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0405

AC:

429

AN:

10602

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0444

AC:

3018

AN:

67954

Other (OTH)

AF:

0.0355

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

231

463

694

926

1157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0301

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.56

PromoterAI

-0.069

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Mutation Taster

=300/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over