Genetic Variant ALDH1A2:p.Ala17Ser (chr15-58065602-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003888.4(ALDH1A2):c.49G>T(p.Ala17Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A17T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALDH1A2
NM_003888.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.06

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31588468).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1A2	NM_003888.4	MANE Select	c.49G>T	p.Ala17Ser	missense	Exon 1 of 13	NP_003879.2
ALDH1A2	NM_170696.3		c.49G>T	p.Ala17Ser	missense	Exon 1 of 12	NP_733797.1	O94788-2
ALDH1A2	NM_001206897.2		c.-112G>T		5_prime_UTR	Exon 1 of 14	NP_001193826.1	O94788-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.49G>T	p.Ala17Ser	missense	Exon 1 of 13	ENSP00000249750.4	O94788-1
ALDH1A2	ENST00000347587.7	TSL:1	c.49G>T	p.Ala17Ser	missense	Exon 1 of 12	ENSP00000309623.3	O94788-2
ALDH1A2	ENST00000888709.1		c.49G>T	p.Ala17Ser	missense	Exon 1 of 14	ENSP00000558768.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458910

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110476

Other (OTH)

AF:

0.0000166

AC:

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.18

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.32

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.12

REVEL

Benign

0.17

Sift

Benign

0.071

Sift4G

Benign

0.12

Polyphen

0.0010

Vest4

0.40

MutPred

0.30

Gain of disorder (P = 0.0249)

MVP

0.62

MPC

0.34

ClinPred

0.64

GERP RS

0.28

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.087

gMVP

0.30

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over