15-58065656-C-T

Position:

• chr15-58065656-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003888.4(ALDH1A2):​c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,579,938 control chromosomes in the GnomAD database, including 1,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (105 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1323 hom.)
• Consequence: ALDH1A2 NM_003888.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.557

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-AS1 (HGNC:27515): (ALDH1A2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-58065656-C-T is Benign according to our data. Variant chr15-58065656-C-T is described in ClinVar as [Benign]. Clinvar id is 3060978.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-58065656-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0304 (4621/152124) while in subpopulation NFE AF= 0.0444 (3018/67954). AF 95% confidence interval is 0.0431. There are 105 homozygotes in gnomad4. There are 2215 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A2	NM_003888.4	c.-6G>A		5_prime_UTR_variant	1/13	ENST00000249750.9
ALDH1A2-AS1	NR_147215.1	n.432C>T		non_coding_transcript_exon_variant	1/3
ALDH1A2	NM_001206897.2	c.-166G>A		5_prime_UTR_variant	1/14
ALDH1A2	NM_170696.3	c.-6G>A		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.-6G>A		5_prime_UTR_variant	1/13	1	NM_003888.4	P1
ALDH1A2-AS1	ENST00000559684.1	n.432C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4621 AN: 152006 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.00785

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0444

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0336 AC: 6763 AN: 201018 Hom.: 151 AF XY: 0.0340 AC XY: 3695 AN XY: 108816

Gnomad AFR exome AF: 0.00774

Gnomad AMR exome AF: 0.0244

Gnomad ASJ exome AF: 0.0693

Gnomad EAS exome AF: 0.000127

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0468

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0411 AC: 58665 AN: 1427814 Hom.: 1323 Cov.: 29 AF XY: 0.0404 AC XY: 28563 AN XY: 707292

Gnomad4 AFR exome AF: 0.00646

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.0656

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0478

Gnomad4 NFE exome AF: 0.0458

Gnomad4 OTH exome AF: 0.0378

GnomAD4 genome AF: 0.0304 AC: 4621 AN: 152124 Hom.: 105 Cov.: 32 AF XY: 0.0298 AC XY: 2215 AN XY: 74388

Gnomad4 AFR AF: 0.00783

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0444

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0301 Hom.: 24

Bravo AF: 0.0292

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALDH1A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3

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: rs34645259; hg19: chr15-58357854;