rs4646660

Positions:

• chr15-100887793-A-C
• chr15-100887793-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000693.4(ALDH1A3):​c.345+81A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,468,906 control chromosomes in the GnomAD database, including 2,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1149 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1154 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-100887793-A-C is Benign according to our data. Variant chr15-100887793-A-C is described in ClinVar as [Benign]. Clinvar id is 1252718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.345+81A>C		intron_variant		ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.345+81A>C		intron_variant			NP_001280744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.345+81A>C		intron_variant		1	NM_000693.4	ENSP00000332256	P1

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12095 AN: 152166 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.00971

Gnomad OTH AF: 0.0761

GnomAD4 exome AF: 0.0190 AC: 24999 AN: 1316622 Hom.: 1154 AF XY: 0.0191 AC XY: 12310 AN XY: 643384

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.0221

Gnomad4 ASJ exome AF: 0.00860

Gnomad4 EAS exome AF: 0.0685

Gnomad4 SAS exome AF: 0.0449

Gnomad4 FIN exome AF: 0.0419

Gnomad4 NFE exome AF: 0.00797

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0795 AC: 12114 AN: 152284 Hom.: 1149 Cov.: 32 AF XY: 0.0803 AC XY: 5983 AN XY: 74464

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.0644

Gnomad4 SAS AF: 0.0503

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.00972

Gnomad4 OTH AF: 0.0758

Alfa AF: 0.0190 Hom.: 199

Bravo AF: 0.0849

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.70
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646660; hg19: chr15-101427998;