15-58065602-C-T

Variant names:

• chr15-58065602-C-T
• rs143084397
• NM_003888.4:c.49G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003888.4(ALDH1A2):​c.49G>A​(p.Ala17Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000628 in 1,611,152 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (7 hom.)
• Consequence: ALDH1A2 NM_003888.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.06
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008425444).
• BP6: Variant 15-58065602-C-T is Benign according to our data. Variant chr15-58065602-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3024882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000633 (924/1458908) while in subpopulation MID AF = 0.0189 (109/5758). AF 95% confidence interval is 0.016. There are 7 homozygotes in GnomAdExome4. There are 468 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003888.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	NM_003888.4	MANE Select	c.49G>A	p.Ala17Thr	missense	Exon 1 of 13	NP_003879.2
	ALDH1A2	NM_170696.3		c.49G>A	p.Ala17Thr	missense	Exon 1 of 12	NP_733797.1	O94788-2
	ALDH1A2	NM_001206897.2		c.-112G>A		5_prime_UTR	Exon 1 of 14	NP_001193826.1	O94788-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.49G>A	p.Ala17Thr	missense	Exon 1 of 13	ENSP00000249750.4	O94788-1
	ALDH1A2	ENST00000347587.7	TSL:1	c.49G>A	p.Ala17Thr	missense	Exon 1 of 12	ENSP00000309623.3	O94788-2
	ALDH1A2	ENST00000888709.1		c.49G>A	p.Ala17Thr	missense	Exon 1 of 14	ENSP00000558768.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.000940 AC: 230 AN: 244738 AF XY: 0.000940

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000761

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000720

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.000633 AC: 924 AN: 1458908 Hom.: 7 Cov.: 30 AF XY: 0.000645 AC XY: 468 AN XY: 725598

African (AFR) AF: 0.000329 AC: 11 AN: 33386

American (AMR) AF: 0.000697 AC: 31 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00992 AC: 257 AN: 25904

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.000233 AC: 20 AN: 85890

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53184

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5758

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1110474

Other (OTH) AF: 0.00174 AC: 105 AN: 60190

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74442

African (AFR) AF: 0.0000962 AC: 4 AN: 41560

American (AMR) AF: 0.000784 AC: 12 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.000669

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ALDH1A2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.15
Sift	Benign	0.094	T
Sift4G	Benign	0.19	T
Polyphen		0.38	B
Vest4		0.24
MVP		0.58
MPC		0.36
ClinPred		0.088	T
GERP RS		0.28
PromoterAI		0.0044	Neutral
Varity_R		0.069
gMVP		0.40
Mutation Taster		=93/7	polymorphism

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: rs143084397; hg19: chr15-58357800;