Genetic Variant NM_003888.4:c.222+73C>T (chr15-58014104-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.195

Publications

4 publications found

Variant links:

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)

ALDH1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ALDH1A2	NM_003888.4 link	c.222+73C>T	intron_variant	Intron 2 of 12	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2 link	c.159+73C>T	intron_variant	Intron 3 of 13		NP_001193826.1
ALDH1A2	NM_170696.3 link	c.222+73C>T	intron_variant	Intron 2 of 11		NP_733797.1
ALDH1A2	NM_170697.3 link	c.-172C>T	upstream_gene_variant			NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9 link	c.222+73C>T		intron_variant	Intron 2 of 12	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2192

AN:

152216

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0192

AC XY:

13961

AN XY:

727076

show subpopulations

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:

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:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0222

AC:

24708

AN:

1111938

Other (OTH)

AF:

0.0170

AC:

1026

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1579

3157

4736

6314

7893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

912

1824

2736

3648

4560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0144

AC:

2192

AN:

152334

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1041

AN XY:

74492

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0255

AC:

271

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0209

AC:

1423

AN:

68032

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0133

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.8

(source)

DANN

Benign

0.63

PhyloP100

0.20

PromoterAI

0.0039

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over