rs4646626

chr15-57963929-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003888.4(ALDH1A2):c.1042G>A(p.Val348Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,794 control chromosomes in the GnomAD database, including 204,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (16446 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188131 hom.)
• Consequence: ALDH1A2 NM_003888.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5779686E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A2	NM_003888.4	c.1042G>A	p.Val348Ile	missense_variant	9/13	ENST00000249750.9
ALDH1A2	NM_001206897.2	c.979G>A	p.Val327Ile	missense_variant	10/14
ALDH1A2	NM_170696.3	c.928G>A	p.Val310Ile	missense_variant	8/12
ALDH1A2	NM_170697.3	c.754G>A	p.Val252Ile	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1042G>A	p.Val348Ile	missense_variant	9/13	1	NM_003888.4	P1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69513 AN: 151936 Hom.: 16438 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.445

GnomAD3 exomes AF: 0.441 AC: 110675 AN: 250872 Hom.: 25867 AF XY: 0.440 AC XY: 59716 AN XY: 135616

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.312

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.531

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.500 AC: 731323 AN: 1461740 Hom.: 188131 Cov.: 60 AF XY: 0.494 AC XY: 359305 AN XY: 727192

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.537

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.457 AC: 69546 AN: 152054 Hom.: 16446 Cov.: 32 AF XY: 0.455 AC XY: 33847 AN XY: 74310

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.529

Gnomad4 OTH AF: 0.443

Alfa AF: 0.504 Hom.: 49780

Bravo AF: 0.446

TwinsUK AF: 0.545 AC: 2020

ALSPAC AF: 0.535 AC: 2063

ESP6500AA AF: 0.378 AC: 1656

ESP6500EA AF: 0.520 AC: 4464

ExAC AF: 0.446 AC: 54147

Asia WGS AF: 0.285 AC: 990 AN: 3478

EpiCase AF: 0.519

EpiControl AF: 0.515

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.33	T;T;T;T;T
MetaRNN	Benign	0.00066	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.71	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.38	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0, 0.011	.;B;B;.;.
Vest4		0.019
MPC		0.30
ClinPred		0.012	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs4646626; hg19: chr15-58256127; COSMIC: COSV51078184;