chr15-100895688-C-T

Position:

• chr15-100895688-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000693.4(ALDH1A3):​c.667-245C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 554,710 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (17 hom., cov: 32)
  • Exomes 𝑓: 0.016 (82 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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=-0.88).
• BP6: Variant 15-100895688-C-T is Benign according to our data. Variant chr15-100895688-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1198426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2067/152342) while in subpopulation NFE AF= 0.0195 (1325/68016). AF 95% confidence interval is 0.0186. There are 17 homozygotes in gnomad4. There are 1035 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.667-245C>T		intron_variant		ENST00000329841.10
ALDH1A3-AS1	NR_135827.1	n.859G>A		non_coding_transcript_exon_variant	2/2
ALDH1A3	NM_001293815.2	c.346-245C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.667-245C>T		intron_variant		1	NM_000693.4	P1
ALDH1A3-AS1	ENST00000656756.1	n.967G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2066 AN: 152226 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0159 AC: 6401 AN: 402368 Hom.: 82 Cov.: 0 AF XY: 0.0154 AC XY: 3242 AN XY: 210194

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.00562

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.0000347

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0136 AC: 2067 AN: 152342 Hom.: 17 Cov.: 32 AF XY: 0.0139 AC XY: 1035 AN XY: 74492

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0371

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0222 Hom.: 3

Bravo AF: 0.0103

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2018	- -
Likely 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	-0.88
CADD	Benign	0.28
DANN	Benign	0.40

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: rs77642169; hg19: chr15-101435893;