15-57965649-C-T

Variant names:

• chr15-57965649-C-T
• rs3784259
• NM_003888.4:c.901+76G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003888.4(ALDH1A2):​c.901+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,047,776 control chromosomes in the GnomAD database, including 125,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16307 hom., cov: 33)
  • Exomes 𝑓: 0.48 (108802 hom.)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0410
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-57965649-C-T is Benign according to our data. Variant chr15-57965649-C-T is described in ClinVar as [Benign]. Clinvar id is 1241238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.901+76G>A		intron_variant	Intron 8 of 12	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.838+76G>A		intron_variant	Intron 9 of 13		NP_001193826.1
ALDH1A2	NM_170696.3	c.787+76G>A		intron_variant	Intron 7 of 11		NP_733797.1
ALDH1A2	NM_170697.3	c.613+76G>A		intron_variant	Intron 6 of 10		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.901+76G>A		intron_variant	Intron 8 of 12	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69213 AN: 151938 Hom.: 16300 Cov.: 33

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.483 AC: 432959 AN: 895720 Hom.: 108802 AF XY: 0.476 AC XY: 223397 AN XY: 468918

African (AFR) AF: 0.378 AC: 8485 AN: 22426

American (AMR) AF: 0.336 AC: 14740 AN: 43862

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 9142 AN: 22586

East Asian (EAS) AF: 0.290 AC: 10731 AN: 37028

South Asian (SAS) AF: 0.289 AC: 21577 AN: 74740

European-Finnish (FIN) AF: 0.537 AC: 28381 AN: 52868

Middle Eastern (MID) AF: 0.402 AC: 1877 AN: 4670

European-Non Finnish (NFE) AF: 0.535 AC: 318635 AN: 595708

Other (OTH) AF: 0.464 AC: 19391 AN: 41832

GnomAD4 genome AF: 0.455 AC: 69241 AN: 152056 Hom.: 16307 Cov.: 33 AF XY: 0.453 AC XY: 33687 AN XY: 74344

African (AFR) AF: 0.376 AC: 15602 AN: 41440

American (AMR) AF: 0.399 AC: 6097 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1351 AN: 3468

East Asian (EAS) AF: 0.304 AC: 1570 AN: 5170

South Asian (SAS) AF: 0.271 AC: 1307 AN: 4816

European-Finnish (FIN) AF: 0.546 AC: 5782 AN: 10582

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35927 AN: 67986

Other (OTH) AF: 0.440 AC: 930 AN: 2112

Alfa AF: 0.493 Hom.: 9424

Bravo AF: 0.444

Asia WGS AF: 0.283 AC: 983 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.26
PhyloP100		0.041
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: rs3784259; hg19: chr15-58257847; COSMIC: COSV51082695; COSMIC: COSV51082695;