15-58014104-G-A

Variant names:

• chr15-58014104-G-A
• rs35667670
• NM_003888.4:c.222+73C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003888.4(ALDH1A2):​c.222+73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,864 control chromosomes in the GnomAD database, including 383 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 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.020 (361 hom.)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 4 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=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0144 (2192/152334) while in subpopulation NFE AF = 0.0209 (1423/68032). AF 95% confidence interval is 0.02. There are 22 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	NM_003888.4	MANE Select	c.222+73C>T		intron	N/A	NP_003879.2
	ALDH1A2	NM_001206897.2		c.159+73C>T		intron	N/A	NP_001193826.1
	ALDH1A2	NM_170696.3		c.222+73C>T		intron	N/A	NP_733797.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A2	ENST00000249750.9	TSL:1 MANE Select	c.222+73C>T		intron	N/A	ENSP00000249750.4
	ALDH1A2	ENST00000347587.7	TSL:1	c.222+73C>T		intron	N/A	ENSP00000309623.3
	ALDH1A2	ENST00000537372.5	TSL:2	c.159+73C>T		intron	N/A	ENSP00000438296.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152216 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0196 AC: 28589 AN: 1461530 Hom.: 361 Cov.: 31 AF XY: 0.0192 AC XY: 13961 AN XY: 727076

African (AFR) AF: 0.00299 AC: 100 AN: 33478

American (AMR) AF: 0.0106 AC: 474 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 596 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00444 AC: 382 AN: 86050

European-Finnish (FIN) AF: 0.0229 AC: 1222 AN: 53358

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5764

European-Non Finnish (NFE) AF: 0.0222 AC: 24708 AN: 1111938

Other (OTH) AF: 0.0170 AC: 1026 AN: 60388

GnomAD4 genome AF: 0.0144 AC: 2192 AN: 152334 Hom.: 22 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74492

African (AFR) AF: 0.00392 AC: 163 AN: 41582

American (AMR) AF: 0.0136 AC: 208 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

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

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0255 AC: 271 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1423 AN: 68032

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0185 Hom.: 42

Bravo AF: 0.0133

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.8
DANN	Benign	0.63
PhyloP100		0.20
PromoterAI		0.0039	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35667670; hg19: chr15-58306302;