15-58065656-C-T

Variant names:

• chr15-58065656-C-T
• rs34645259
• NM_003888.4:c.-6G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 0.557
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -13 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 VariationId is 3060978.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.-6G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2-AS1	NR_147215.1	n.432C>T		non_coding_transcript_exon_variant	Exon 1 of 3
ALDH1A2	NM_001206897.2	c.-166G>A		5_prime_UTR_variant	Exon 1 of 14		NP_001193826.1
ALDH1A2	NM_170696.3	c.-6G>A		5_prime_UTR_variant	Exon 1 of 12		NP_733797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.-6G>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_003888.4	ENSP00000249750.4

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

GnomAD2 exomes AF: 0.0336 AC: 6763 AN: 201018 AF XY: 0.0340

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 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

African (AFR) AF: 0.00646 AC: 211 AN: 32678

American (AMR) AF: 0.0246 AC: 1014 AN: 41214

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 1590 AN: 24236

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38838

South Asian (SAS) AF: 0.0119 AC: 971 AN: 81650

European-Finnish (FIN) AF: 0.0478 AC: 2459 AN: 51394

Middle Eastern (MID) AF: 0.0245 AC: 138 AN: 5626

European-Non Finnish (NFE) AF: 0.0458 AC: 50058 AN: 1093450

Other (OTH) AF: 0.0378 AC: 2219 AN: 58728

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

African (AFR) AF: 0.00783 AC: 325 AN: 41532

American (AMR) AF: 0.0309 AC: 473 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0717 AC: 249 AN: 3472

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5126

South Asian (SAS) AF: 0.00851 AC: 41 AN: 4820

European-Finnish (FIN) AF: 0.0405 AC: 429 AN: 10602

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0444 AC: 3018 AN: 67954

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

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: no assertion criteria provided

Submissions by phenotype

ALDH1A2-related disorder Benign:1

May 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.56
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs34645259; hg19: chr15-58357854;