15-100879950-A-G

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.43A>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00859 in 1,472,488 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (74 hom.)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.655

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 (MetaRNN=0.0028638542).
• BP6: Variant 15-100879950-A-G is Benign according to our data. Variant chr15-100879950-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-100879950-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0057 (865/151884) while in subpopulation NFE AF= 0.00948 (644/67906). AF 95% confidence interval is 0.00888. There are 7 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.43A>G	p.Arg15Gly	missense_variant	1/13	ENST00000329841.10
ALDH1A3	NM_001293815.2	c.43A>G	p.Arg15Gly	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.43A>G	p.Arg15Gly	missense_variant	1/13	1	NM_000693.4	P1

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 865 AN: 151776 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000861

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00950

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00463 AC: 389 AN: 84108 Hom.: 0 AF XY: 0.00455 AC XY: 216 AN XY: 47456

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.000828

Gnomad ASJ exome AF: 0.00384

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00166

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00516

GnomAD4 exome AF: 0.00892 AC: 11785 AN: 1320604 Hom.: 74 Cov.: 30 AF XY: 0.00861 AC XY: 5601 AN XY: 650560

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00667

GnomAD4 genome AF: 0.00570 AC: 865 AN: 151884 Hom.: 7 Cov.: 33 AF XY: 0.00457 AC XY: 339 AN XY: 74246

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000861

Gnomad4 NFE AF: 0.00948

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00799 Hom.: 3

Bravo AF: 0.00581

ESP6500AA AF: 0.00138 AC: 4

ESP6500EA AF: 0.00499 AC: 27

ExAC AF: 0.00170 AC: 45

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ALDH1A3: BS2 -

Isolated microphthalmia 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 24, 2022	- -

ALDH1A3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	12
Dann	Benign	0.62
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.97	N;D;N
REVEL	Benign	0.11
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.093
MVP		0.46
MPC		0.71
ClinPred		0.00030	T
GERP RS		-3.5
Varity_R		0.072
gMVP		0.39

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: rs1130737; hg19: chr15-101420155; COSMIC: COSV105210727;