15-100905610-A-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000693.4(ALDH1A3):​c.1156A>G​(p.Met386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,613,692 control chromosomes in the GnomAD database, including 4,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1766 hom., cov: 32)
Exomes 𝑓: 0.036 ( 2332 hom. )

Consequence

ALDH1A3
NM_000693.4 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.161

Publications

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

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=0.0027904809).
BP6
Variant 15-100905610-A-G is Benign according to our data. Variant chr15-100905610-A-G is described in ClinVar as [Benign]. Clinvar id is 256760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALDH1A3NM_000693.4 linkc.1156A>G p.Met386Val missense_variant Exon 10 of 13 ENST00000329841.10 NP_000684.2 P47895A0A024RC95
ALDH1A3NM_001293815.2 linkc.835A>G p.Met279Val missense_variant Exon 7 of 10 NP_001280744.1 P47895H0Y2X5Q7Z3A2
ALDH1A3-AS1NR_135827.1 linkn.481-9544T>C intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALDH1A3ENST00000329841.10 linkc.1156A>G p.Met386Val missense_variant Exon 10 of 13 1 NM_000693.4 ENSP00000332256.5 P47895

Frequencies

GnomAD3 genomes
AF:
0.105
AC:
16010
AN:
152092
Hom.:
1755
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.282
Gnomad AMI
AF:
0.0143
Gnomad AMR
AF:
0.0630
Gnomad ASJ
AF:
0.0637
Gnomad EAS
AF:
0.0666
Gnomad SAS
AF:
0.0555
Gnomad FIN
AF:
0.0533
Gnomad MID
AF:
0.0949
Gnomad NFE
AF:
0.0255
Gnomad OTH
AF:
0.103
GnomAD2 exomes
AF:
0.0539
AC:
13524
AN:
250724
AF XY:
0.0507
show subpopulations
Gnomad AFR exome
AF:
0.286
Gnomad AMR exome
AF:
0.0336
Gnomad ASJ exome
AF:
0.0693
Gnomad EAS exome
AF:
0.0627
Gnomad FIN exome
AF:
0.0442
Gnomad NFE exome
AF:
0.0275
Gnomad OTH exome
AF:
0.0483
GnomAD4 exome
AF:
0.0357
AC:
52208
AN:
1461484
Hom.:
2332
Cov.:
31
AF XY:
0.0356
AC XY:
25915
AN XY:
727028
show subpopulations
African (AFR)
AF:
0.291
AC:
9734
AN:
33440
American (AMR)
AF:
0.0368
AC:
1642
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.0655
AC:
1711
AN:
26114
East Asian (EAS)
AF:
0.0725
AC:
2878
AN:
39694
South Asian (SAS)
AF:
0.0503
AC:
4337
AN:
86192
European-Finnish (FIN)
AF:
0.0445
AC:
2377
AN:
53412
Middle Eastern (MID)
AF:
0.0930
AC:
536
AN:
5762
European-Non Finnish (NFE)
AF:
0.0232
AC:
25809
AN:
1111852
Other (OTH)
AF:
0.0527
AC:
3184
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
2755
5510
8266
11021
13776
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1158
2316
3474
4632
5790
<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:
0.105
AC:
16055
AN:
152208
Hom.:
1766
Cov.:
32
AF XY:
0.106
AC XY:
7898
AN XY:
74420
show subpopulations
African (AFR)
AF:
0.282
AC:
11701
AN:
41494
American (AMR)
AF:
0.0628
AC:
961
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.0637
AC:
221
AN:
3470
East Asian (EAS)
AF:
0.0662
AC:
342
AN:
5168
South Asian (SAS)
AF:
0.0551
AC:
266
AN:
4826
European-Finnish (FIN)
AF:
0.0533
AC:
566
AN:
10614
Middle Eastern (MID)
AF:
0.0952
AC:
28
AN:
294
European-Non Finnish (NFE)
AF:
0.0255
AC:
1734
AN:
68022
Other (OTH)
AF:
0.106
AC:
223
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
624
1248
1871
2495
3119
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
156
312
468
624
780
<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:
0.0469
Hom.:
2268
Bravo
AF:
0.113
TwinsUK
AF:
0.0205
AC:
76
ALSPAC
AF:
0.0226
AC:
87
ESP6500AA
AF:
0.275
AC:
1212
ESP6500EA
AF:
0.0305
AC:
262
ExAC
AF:
0.0586
AC:
7113
Asia WGS
AF:
0.0810
AC:
284
AN:
3478
EpiCase
AF:
0.0280
EpiControl
AF:
0.0326

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Aug 03, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Isolated microphthalmia 8 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
0.21
DANN
Benign
0.56
DEOGEN2
Benign
0.18
T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.73
T;T
MetaRNN
Benign
0.0028
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-1.2
N;.
PhyloP100
-0.16
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.39
N;N
REVEL
Benign
0.19
Sift
Benign
0.51
T;T
Sift4G
Benign
0.50
T;T
Polyphen
0.0
B;.
Vest4
0.042
MPC
0.56
ClinPred
0.0010
T
GERP RS
-1.3
Varity_R
0.12
gMVP
0.46
Mutation Taster
=98/2
polymorphism (auto)

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

Other links and lift over

dbSNP: rs3803430; hg19: chr15-101445815; COSMIC: COSV60901674; API