15-57961071-T-G

Variant names:

• chr15-57961071-T-G
• rs3784260
• NM_003888.4:c.1409+66A>C

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.1409+66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,589,194 control chromosomes in the GnomAD database, including 148,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12233 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136262 hom.)
• Consequence: ALDH1A2 NM_003888.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• Publications: 14 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=-0.85).
• BP6: Variant 15-57961071-T-G is Benign according to our data. Variant chr15-57961071-T-G is described in ClinVar as Benign. ClinVar VariationId is 1226239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A2	NM_003888.4	c.1409+66A>C		intron_variant	Intron 11 of 12	ENST00000249750.9	NP_003879.2
ALDH1A2	NM_001206897.2	c.1346+66A>C		intron_variant	Intron 12 of 13		NP_001193826.1
ALDH1A2	NM_170696.3	c.1295+66A>C		intron_variant	Intron 10 of 11		NP_733797.1
ALDH1A2	NM_170697.3	c.1121+66A>C		intron_variant	Intron 9 of 10		NP_733798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A2	ENST00000249750.9	c.1409+66A>C		intron_variant	Intron 11 of 12	1	NM_003888.4	ENSP00000249750.4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59808 AN: 151876 Hom.: 12229 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.426 AC: 612344 AN: 1437200 Hom.: 136262 Cov.: 29 AF XY: 0.419 AC XY: 300441 AN XY: 716276

African (AFR) AF: 0.337 AC: 11125 AN: 33022

American (AMR) AF: 0.263 AC: 11731 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9066 AN: 25994

East Asian (EAS) AF: 0.160 AC: 6340 AN: 39578

South Asian (SAS) AF: 0.201 AC: 17212 AN: 85634

European-Finnish (FIN) AF: 0.464 AC: 23180 AN: 49952

Middle Eastern (MID) AF: 0.304 AC: 1744 AN: 5738

European-Non Finnish (NFE) AF: 0.465 AC: 508184 AN: 1093080

Other (OTH) AF: 0.398 AC: 23762 AN: 59674

GnomAD4 genome AF: 0.394 AC: 59834 AN: 151994 Hom.: 12233 Cov.: 32 AF XY: 0.390 AC XY: 28941 AN XY: 74292

African (AFR) AF: 0.343 AC: 14242 AN: 41474

American (AMR) AF: 0.325 AC: 4970 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3470

East Asian (EAS) AF: 0.184 AC: 952 AN: 5176

South Asian (SAS) AF: 0.180 AC: 867 AN: 4808

European-Finnish (FIN) AF: 0.474 AC: 4996 AN: 10544

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31305 AN: 67934

Other (OTH) AF: 0.369 AC: 777 AN: 2104

Alfa AF: 0.426 Hom.: 22746

Bravo AF: 0.384

Asia WGS AF: 0.186 AC: 645 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	-0.85
CADD	Benign	0.14
DANN	Benign	0.66
PhyloP100		-1.1
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: rs3784260; hg19: chr15-58253269; COSMIC: COSV51081998;