15-57955251-C-T

Position:

• chr15-57955251-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003888.4(ALDH1A2):​c.1503G>A​(p.Arg501Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,060 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: ALDH1A2 NM_003888.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.407

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-57955251-C-T is Benign according to our data. Variant chr15-57955251-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1675576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-57955251-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.407 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.1503G>A	p.Arg501Arg	synonymous_variant	13/13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.1440G>A	p.Arg480Arg	synonymous_variant	14/14		NP_001193826.1
ALDH1A2	NM_170696.3	c.1389G>A	p.Arg463Arg	synonymous_variant	12/12		NP_733797.1
ALDH1A2	NM_170697.3	c.1215G>A	p.Arg405Arg	synonymous_variant	11/11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1503G>A	p.Arg501Arg	synonymous_variant	13/13	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152074 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00160 AC: 399 AN: 249612 Hom.: 2 AF XY: 0.00176 AC XY: 237 AN XY: 135042

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00125 AC: 1826 AN: 1461868 Hom.: 6 Cov.: 30 AF XY: 0.00138 AC XY: 1006 AN XY: 727238

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.00204

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152192 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74396

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00119

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ALDH1A2: BP4, BP7 -

ALDH1A2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.79
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139785128; hg19: chr15-58247449;