15-100883261-G-C

Variant names:

• chr15-100883261-G-C
• rs4646651
• NM_000693.4:c.100-2006G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000693.4(ALDH1A3):​c.100-2006G>C 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 151,968 control chromosomes in the GnomAD database, including 4,923 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 (4923 hom., cov: 33)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• isolated microphthalmia 8

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	NM_000693.4	MANE Select	c.100-2006G>C		intron	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.100-2006G>C		intron	N/A	NP_001280744.1	H0Y2X5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.100-2006G>C		intron	N/A	ENSP00000332256.5	P47895
	ALDH1A3	ENST00000346623.6	TSL:1	c.100-2006G>C		intron	N/A	ENSP00000343294.6	H0Y2X5
	ALDH1A3	ENST00000560555.1	TSL:1	n.160-2006G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36447 AN: 151848 Hom.: 4909 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.240 AC: 36496 AN: 151968 Hom.: 4923 Cov.: 33 AF XY: 0.244 AC XY: 18119 AN XY: 74262

African (AFR) AF: 0.322 AC: 13332 AN: 41426

American (AMR) AF: 0.270 AC: 4131 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 473 AN: 3464

East Asian (EAS) AF: 0.546 AC: 2823 AN: 5168

South Asian (SAS) AF: 0.176 AC: 843 AN: 4802

European-Finnish (FIN) AF: 0.215 AC: 2267 AN: 10546

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.177 AC: 12035 AN: 67968

Other (OTH) AF: 0.230 AC: 486 AN: 2110

Alfa AF: 0.215 Hom.: 465

Bravo AF: 0.251

Asia WGS AF: 0.348 AC: 1212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.74
PhyloP100		1.1
Mutation Taster		=98/2	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: rs4646651; hg19: chr15-101423466;