rs35251510

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003888.4(ALDH1A2):c.1254C>A(p.Ile418Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,738 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 67 hom. )

Consequence

ALDH1A2
NM_003888.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.99

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 15-57961292-G-T is Benign according to our data. Variant chr15-57961292-G-T is described in ClinVar as Benign. ClinVar VariationId is 779960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.99 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00633 (964/152262) while in subpopulation AFR AF = 0.0164 (682/41536). AF 95% confidence interval is 0.0154. There are 8 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALDH1A2	NM_003888.4 link	c.1254C>A	p.Ile418Ile	splice_region_variant, synonymous_variant	Exon 11 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2 link	c.1191C>A	p.Ile397Ile	splice_region_variant, synonymous_variant	Exon 12 of 14		NP_001193826.1
ALDH1A2	NM_170696.3 link	c.1140C>A	p.Ile380Ile	splice_region_variant, synonymous_variant	Exon 10 of 12		NP_733797.1
ALDH1A2	NM_170697.3 link	c.966C>A	p.Ile322Ile	splice_region_variant, synonymous_variant	Exon 9 of 11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9 link	c.1254C>A	p.Ile418Ile	splice_region_variant, synonymous_variant	Exon 11 of 13	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

961

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0121

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00253

AC:

634

AN:

250782

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00267

AC:

3898

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

1860

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.0198

AC:

664

AN:

33476

American (AMR)

AF:

0.00335

AC:

150

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

26132

East Asian (EAS)

AF:

0.0337

AC:

1336

AN:

39692

South Asian (SAS)

AF:

0.000533

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000753

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00118

AC:

1312

AN:

1111934

Other (OTH)

AF:

0.00397

AC:

240

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

202

404

606

808

1010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.00633

AC:

964

AN:

152262

Hom.:

Cov.:

AF XY:

0.00594

AC XY:

442

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0164

AC:

682

AN:

41536

American (AMR)

AF:

0.00425

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.0121

AC:

AN:

5188

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00175

AC:

119

AN:

68024

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00394

Hom.:

Bravo

AF:

0.00688

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALDH1A2-related disorder

Benign:1

Feb 22, 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

-0.28

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=88/12

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over