15-57963929-C-T

Variant names:

• chr15-57963929-C-T
• rs4646626
• NM_003888.4:c.1042G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.1042G>A	p.Val348Ile	missense_variant	Exon 9 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.979G>A	p.Val327Ile	missense_variant	Exon 10 of 14		NP_001193826.1
ALDH1A2	NM_170696.3	c.928G>A	p.Val310Ile	missense_variant	Exon 8 of 12		NP_733797.1
ALDH1A2	NM_170697.3	c.754G>A	p.Val252Ile	missense_variant	Exon 7 of 11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1042G>A	p.Val348Ile	missense_variant	Exon 9 of 13	1	NM_003888.4	ENSP00000249750.4

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

GnomAD2 exomes AF: 0.441 AC: 110675 AN: 250872 AF XY: 0.440

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 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

African (AFR) AF: 0.377 AC: 12611 AN: 33476

American (AMR) AF: 0.337 AC: 15077 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 10564 AN: 26136

East Asian (EAS) AF: 0.293 AC: 11630 AN: 39686

South Asian (SAS) AF: 0.290 AC: 25054 AN: 86256

European-Finnish (FIN) AF: 0.540 AC: 28842 AN: 53416

Middle Eastern (MID) AF: 0.397 AC: 2288 AN: 5768

European-Non Finnish (NFE) AF: 0.537 AC: 597084 AN: 1111892

Other (OTH) AF: 0.467 AC: 28173 AN: 60388

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

African (AFR) AF: 0.381 AC: 15796 AN: 41474

American (AMR) AF: 0.400 AC: 6123 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1351 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1574 AN: 5138

South Asian (SAS) AF: 0.273 AC: 1318 AN: 4824

European-Finnish (FIN) AF: 0.550 AC: 5822 AN: 10594

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35955 AN: 67938

Other (OTH) AF: 0.443 AC: 934 AN: 2110

Alfa AF: 0.502 Hom.: 90313

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
DEOGEN2	Benign	0.24	.;T;.;T;.
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
MutationAssessor	Benign	1.9	.;L;.;.;.
PhyloP100		2.0
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
Mutation Taster		=99/1	polymorphism (auto)

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;