rs4646642

Variant names:

• chr15-57954718-A-G
• rs4646642
• ENST00000560312.5:n.1857T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000560312.5(ALDH1A2):​n.1857T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 188,732 control chromosomes in the GnomAD database, including 21,345 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17390 hom., cov: 32)
  • Exomes 𝑓: 0.44 (3955 hom.)
• Consequence: ALDH1A2 ENST00000560312.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.*479T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.*479T>C		3_prime_UTR_variant	Exon 14 of 14		NP_001193826.1
ALDH1A2	NM_170696.3	c.*479T>C		3_prime_UTR_variant	Exon 12 of 12		NP_733797.1
ALDH1A2	NM_170697.3	c.*479T>C		3_prime_UTR_variant	Exon 11 of 11		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.*479T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71519 AN: 151800 Hom.: 17384 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.442 AC: 16282 AN: 36814 Hom.: 3955 Cov.: 0 AF XY: 0.433 AC XY: 8181 AN XY: 18886

African (AFR) AF: 0.339 AC: 590 AN: 1740

American (AMR) AF: 0.378 AC: 1390 AN: 3674

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 313 AN: 756

East Asian (EAS) AF: 0.307 AC: 1100 AN: 3588

South Asian (SAS) AF: 0.278 AC: 1129 AN: 4054

European-Finnish (FIN) AF: 0.514 AC: 716 AN: 1394

Middle Eastern (MID) AF: 0.348 AC: 39 AN: 112

European-Non Finnish (NFE) AF: 0.517 AC: 10234 AN: 19806

Other (OTH) AF: 0.456 AC: 771 AN: 1690

GnomAD4 genome AF: 0.471 AC: 71547 AN: 151918 Hom.: 17390 Cov.: 32 AF XY: 0.468 AC XY: 34729 AN XY: 74232

African (AFR) AF: 0.391 AC: 16197 AN: 41402

American (AMR) AF: 0.411 AC: 6276 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1389 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1663 AN: 5158

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4818

European-Finnish (FIN) AF: 0.556 AC: 5868 AN: 10554

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.547 AC: 37156 AN: 67946

Other (OTH) AF: 0.453 AC: 953 AN: 2106

Alfa AF: 0.513 Hom.: 45591

Bravo AF: 0.459

Asia WGS AF: 0.294 AC: 1021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs4646642; hg19: chr15-58246916; COSMIC: COSV51082898; COSMIC: COSV51082898;