NM_000693.4:c.346-1021A>G

Variant names:

• chr15-100891489-A-G
• rs4646662
• NM_000693.4:c.346-1021A>G

Variant summary

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

The NM_000693.4(ALDH1A3):​c.346-1021A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,260 control chromosomes in the GnomAD database, including 2,353 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 0.15 (2353 hom., cov: 33)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92
• Publications: 1 publications found

Genes affected

ALDH1A3 (HGNC:409): (aldehyde dehydrogenase 1 family member A3) This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ALDH1A3 Gene-Disease associations (from GenCC):

• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• isolated microphthalmia 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.346-1021A>G		intron_variant	Intron 3 of 12	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.345+3777A>G		intron_variant	Intron 3 of 9		NP_001280744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.346-1021A>G		intron_variant	Intron 3 of 12	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22630 AN: 152142 Hom.: 2352 Cov.: 33

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.147

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22639 AN: 152260 Hom.: 2353 Cov.: 33 AF XY: 0.152 AC XY: 11318 AN XY: 74454

African (AFR) AF: 0.0387 AC: 1609 AN: 41560

American (AMR) AF: 0.235 AC: 3600 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2432 AN: 5166

South Asian (SAS) AF: 0.127 AC: 611 AN: 4826

European-Finnish (FIN) AF: 0.179 AC: 1902 AN: 10610

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11630 AN: 68006

Other (OTH) AF: 0.148 AC: 313 AN: 2116

Alfa AF: 0.157 Hom.: 271

Bravo AF: 0.150

Asia WGS AF: 0.292 AC: 1014 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.28
DANN	Benign	0.42
PhyloP100		-2.9
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: rs4646662; hg19: chr15-101431694;