15-100892476-T-C

Position:

• chr15-100892476-T-C

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.346-34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,607,842 control chromosomes in the GnomAD database, including 995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (477 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (518 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

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-AS1 (HGNC:55416): (ALDH1A3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-100892476-T-C is Benign according to our data. Variant chr15-100892476-T-C is described in ClinVar as [Benign]. Clinvar id is 1281056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.346-34T>C		intron_variant		ENST00000329841.10
ALDH1A3-AS1	NR_135827.1	n.4071A>G		non_coding_transcript_exon_variant	2/2
ALDH1A3	NM_001293815.2	c.346-3457T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.346-34T>C		intron_variant		1	NM_000693.4	P1
ALDH1A3-AS1	ENST00000656756.1	n.4179A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7234 AN: 152158 Hom.: 477 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0178 AC: 4358 AN: 245346 Hom.: 201 AF XY: 0.0148 AC XY: 1967 AN XY: 132580

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.00880

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.0108

Gnomad SAS exome AF: 0.00748

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00830 AC: 12077 AN: 1455566 Hom.: 518 Cov.: 30 AF XY: 0.00787 AC XY: 5697 AN XY: 723972

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.00968

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0423

Gnomad4 SAS exome AF: 0.00812

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0477 AC: 7256 AN: 152276 Hom.: 477 Cov.: 33 AF XY: 0.0472 AC XY: 3512 AN XY: 74456

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0353 Hom.: 76

Bravo AF: 0.0520

Asia WGS AF: 0.0410 AC: 142 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	clinical testing	GeneDx	Oct 22, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3809521; hg19: chr15-101432681;