rs4646649

Variant names:

• chr15-100882522-G-A
• rs4646649
• NM_000693.4:c.99+2516G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-100882522-G-A
• chr15-100882522-G-T

Variant summary

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

The NM_000693.4(ALDH1A3):​c.99+2516G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,076 control chromosomes in the GnomAD database, including 4,886 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 0.24 (4886 hom., cov: 33)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• Publications: 4 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=-0.66).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.99+2516G>A		intron_variant	Intron 1 of 12	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.99+2516G>A		intron_variant	Intron 1 of 9		NP_001280744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.99+2516G>A		intron_variant	Intron 1 of 12	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36426 AN: 151958 Hom.: 4875 Cov.: 33

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.240 AC: 36477 AN: 152076 Hom.: 4886 Cov.: 33 AF XY: 0.245 AC XY: 18221 AN XY: 74348

African (AFR) AF: 0.315 AC: 13041 AN: 41458

American (AMR) AF: 0.268 AC: 4101 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3466

East Asian (EAS) AF: 0.545 AC: 2819 AN: 5172

South Asian (SAS) AF: 0.175 AC: 844 AN: 4826

European-Finnish (FIN) AF: 0.242 AC: 2553 AN: 10558

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12066 AN: 67982

Other (OTH) AF: 0.224 AC: 475 AN: 2116

Alfa AF: 0.198 Hom.: 12788

Bravo AF: 0.248

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4646649; hg19: chr15-101422727;