15-57962045-G-T

Variant names:

• chr15-57962045-G-T
• NM_003888.4:c.1218C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003888.4(ALDH1A2):​c.1218C>A​(p.Asn406Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1A2 NM_003888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.199

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.1218C>A	p.Asn406Lys	missense_variant	Exon 10 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.1155C>A	p.Asn385Lys	missense_variant	Exon 11 of 14		NP_001193826.1
ALDH1A2	NM_170696.3	c.1104C>A	p.Asn368Lys	missense_variant	Exon 9 of 12		NP_733797.1
ALDH1A2	NM_170697.3	c.930C>A	p.Asn310Lys	missense_variant	Exon 8 of 11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1218C>A	p.Asn406Lys	missense_variant	Exon 10 of 13	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1218C>A (p.N406K) alteration is located in exon 10 (coding exon 10) of the ALDH1A2 gene. This alteration results from a C to A substitution at nucleotide position 1218, causing the asparagine (N) at amino acid position 406 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;.;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.020	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.
Vest4		0.70
MutPred		0.72		.;Gain of methylation at N406 (P = 0.0102);.;.;.;
MVP		0.52
MPC		0.89
ClinPred		0.97	D
GERP RS		-1.9
Varity_R		0.81
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-58254243;