15-100879950-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 14/21 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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

isolated anophthalmia-microphthalmia syndrome
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
isolated microphthalmia 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ALDH1A3 links:

LOC124903575 (HGNC:):

LOC124903575 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.2359 (below the threshold of 3.09). Trascript score misZ: 2.2507 (below the threshold of 3.09). GenCC associations: The gene is linked to isolated anophthalmia-microphthalmia syndrome, isolated microphthalmia 8.

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 Benign/Likely_benign. ClinVar VariationId is 235693.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 = 0.0057 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4 link	c.43A>G	p.Arg15Gly	missense_variant	Exon 1 of 13	ENST00000329841.10	NP_000684.2	P47895A0A024RC95
ALDH1A3	NM_001293815.2 link	c.43A>G	p.Arg15Gly	missense_variant	Exon 1 of 10		NP_001280744.1	P47895H0Y2X5Q7Z3A2
LOC124903575	XM_047433433.1 link	c.-147T>C		upstream_gene_variant			XP_047289389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10 link	c.43A>G	p.Arg15Gly	missense_variant	Exon 1 of 13	1	NM_000693.4	ENSP00000332256.5		P47895

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

GnomAD2 exomes

AF:

0.00463

AC:

389

AN:

84108

AF XY:

0.00455

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 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

African (AFR)

AF:

0.00101

AC:

AN:

26726

American (AMR)

AF:

0.00124

AC:

AN:

26638

Ashkenazi Jewish (ASJ)

AF:

0.00362

AC:

AN:

23206

East Asian (EAS)

AF:

0.00

AC:

AN:

27956

South Asian (SAS)

AF:

0.00137

AC:

AN:

72388

European-Finnish (FIN)

AF:

0.00117

AC:

AN:

41852

Middle Eastern (MID)

AF:

0.000975

AC:

AN:

5130

European-Non Finnish (NFE)

AF:

0.0107

AC:

11127

AN:

1042546

Other (OTH)

AF:

0.00667

AC:

361

AN:

54162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

652

1303

1955

2606

3258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

454

908

1362

1816

2270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00570

AC:

865

AN:

151884

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

339

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41514

American (AMR)

AF:

0.00255

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000861

AC:

AN:

10458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00948

AC:

644

AN:

67906

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00786

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

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALDH1A3: BS2 -

Jul 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 09, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Isolated microphthalmia 8

Benign:2

Jan 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALDH1A3-related disorder

Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

0.66

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

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.072

gMVP

0.39

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over