rs16939660

Variant names:

• chr15-58010689-T-C
• rs16939660
• NM_003888.4:c.453A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003888.4(ALDH1A2):​c.453A>G​(p.Ala151Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,613,522 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (80 hom.)
• Consequence: ALDH1A2 NM_003888.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.111
• Publications: 9 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 Gene-Disease associations (from GenCC):

• diaphragmatic hernia 4, with cardiovascular defects

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-58010689-T-C is Benign according to our data. Variant chr15-58010689-T-C is described in ClinVar as Benign. ClinVar VariationId is 788449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.111 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2139/152250) while in subpopulation AFR AF = 0.0327 (1360/41546). AF 95% confidence interval is 0.0313. There are 25 homozygotes in GnomAd4. There are 1016 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.453A>G	p.Ala151Ala	synonymous_variant	Exon 4 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.390A>G	p.Ala130Ala	synonymous_variant	Exon 5 of 14		NP_001193826.1
ALDH1A2	NM_170696.3	c.453A>G	p.Ala151Ala	synonymous_variant	Exon 4 of 12		NP_733797.1
ALDH1A2	NM_170697.3	c.165A>G	p.Ala55Ala	synonymous_variant	Exon 2 of 11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.453A>G	p.Ala151Ala	synonymous_variant	Exon 4 of 13	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2139 AN: 152132 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00835 AC: 2098 AN: 251216 AF XY: 0.00780

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00944

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00921

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00811 AC: 11845 AN: 1461272 Hom.: 80 Cov.: 31 AF XY: 0.00785 AC XY: 5709 AN XY: 726984

African (AFR) AF: 0.0334 AC: 1116 AN: 33452

American (AMR) AF: 0.00966 AC: 432 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 186 AN: 26114

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86246

European-Finnish (FIN) AF: 0.00264 AC: 141 AN: 53406

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5762

European-Non Finnish (NFE) AF: 0.00828 AC: 9200 AN: 1111532

Other (OTH) AF: 0.00926 AC: 559 AN: 60362

GnomAD4 genome AF: 0.0140 AC: 2139 AN: 152250 Hom.: 25 Cov.: 32 AF XY: 0.0137 AC XY: 1016 AN XY: 74430

African (AFR) AF: 0.0327 AC: 1360 AN: 41546

American (AMR) AF: 0.0117 AC: 179 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00773 AC: 526 AN: 68012

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.0111 Hom.: 47

Bravo AF: 0.0160

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00823

EpiControl AF: 0.00901

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALDH1A2-related disorder Benign:1

Mar 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.46
CADD	Benign	10
DANN	Benign	0.63
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16939660; hg19: chr15-58302887;