rs1130737

Positions:

chr15-100879950-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.655

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 7 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00455

AC XY:

216

AN XY:

47456

show subpopulations

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.:

Cov.:

AF XY:

0.00861

AC XY:

5601

AN XY:

650560

show subpopulations

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.:

Cov.:

AF XY:

0.00457

AC XY:

339

AN XY:

74246

show subpopulations

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.:

Bravo

AF:

0.00581

ESP6500AA

AF:

0.00138

AC:

ESP6500EA

AF:

0.00499

AC:

ExAC

AF:

0.00170

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ALDH1A3: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Isolated microphthalmia 8

Benign:2

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

ALDH1A3-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

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

LIST_S2

Benign

0.58

T;T;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over