rs35251510

chr15-57961292-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003888.4(ALDH1A2):c.1254C>A(p.Ile418=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,738 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (67 hom.)
• Consequence: ALDH1A2 NM_003888.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.99

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-57961292-G-T is Benign according to our data. Variant chr15-57961292-G-T is described in ClinVar as [Benign]. Clinvar id is 779960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-57961292-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00633 (964/152262) while in subpopulation AFR AF= 0.0164 (682/41536). AF 95% confidence interval is 0.0154. There are 8 homozygotes in gnomad4. There are 442 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A2	NM_003888.4	c.1254C>A	p.Ile418=	splice_region_variant, synonymous_variant	11/13	ENST00000249750.9
ALDH1A2	NM_001206897.2	c.1191C>A	p.Ile397=	splice_region_variant, synonymous_variant	12/14
ALDH1A2	NM_170696.3	c.1140C>A	p.Ile380=	splice_region_variant, synonymous_variant	10/12
ALDH1A2	NM_170697.3	c.966C>A	p.Ile322=	splice_region_variant, synonymous_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1254C>A	p.Ile418=	splice_region_variant, synonymous_variant	11/13	1	NM_003888.4	P1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 961 AN: 152144 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00253 AC: 634 AN: 250782 Hom.: 1 AF XY: 0.00214 AC XY: 290 AN XY: 135584

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00267 AC: 3898 AN: 1461476 Hom.: 67 Cov.: 32 AF XY: 0.00256 AC XY: 1860 AN XY: 727088

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0337

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00633 AC: 964 AN: 152262 Hom.: 8 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74438

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0121

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00309 Hom.: 4

Bravo AF: 0.00688

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALDH1A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.89
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: rs35251510; hg19: chr15-58253490;