NM_003888.4:c.22A>C

Variant names:

• chr15-58065629-T-G
• rs1257189989
• NM_003888.4:c.22A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003888.4(ALDH1A2):​c.22A>C​(p.Met8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,604,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALDH1A2 NM_003888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10607821).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	NM_003888.4	MANE Select	c.22A>C	p.Met8Leu	missense	Exon 1 of 13	NP_003879.2
	ALDH1A2	NM_001206897.2		c.-139A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001193826.1	O94788-3
	ALDH1A2	NM_170696.3		c.22A>C	p.Met8Leu	missense	Exon 1 of 12	NP_733797.1	O94788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.22A>C	p.Met8Leu	missense	Exon 1 of 13	ENSP00000249750.4	O94788-1
	ALDH1A2	ENST00000347587.7	TSL:1	c.22A>C	p.Met8Leu	missense	Exon 1 of 12	ENSP00000309623.3	O94788-2
	ALDH1A2	ENST00000537372.5	TSL:2	c.-139A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000438296.1	O94788-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452252 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721750

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 84832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106892

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.76	N
PhyloP100		2.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.11
Sift	Benign	0.91	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.17		Loss of methylation at K5 (P = 0.0517)
MVP		0.25
MPC		0.34
ClinPred		0.25	T
GERP RS		3.3
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.12
gMVP		0.41
Mutation Taster		=277/23	polymorphism

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

Other links and lift over

dbSNP: rs1257189989; hg19: chr15-58357827;