15-100885290-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_000693.4(ALDH1A3):​c.123C>G​(p.His41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ALDH1A3
NM_000693.4 missense

Scores

5
14

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -4.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007013142).
BP6
Variant 15-100885290-C-G is Benign according to our data. Variant chr15-100885290-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 772098.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0011 (167/152268) while in subpopulation AFR AF= 0.00376 (156/41542). AF 95% confidence interval is 0.00327. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALDH1A3NM_000693.4 linkc.123C>G p.His41Gln missense_variant Exon 2 of 13 ENST00000329841.10 NP_000684.2 P47895A0A024RC95
ALDH1A3NM_001293815.2 linkc.123C>G p.His41Gln missense_variant Exon 2 of 10 NP_001280744.1 P47895H0Y2X5Q7Z3A2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALDH1A3ENST00000329841.10 linkc.123C>G p.His41Gln missense_variant Exon 2 of 13 1 NM_000693.4 ENSP00000332256.5 P47895

Frequencies

GnomAD3 genomes
AF:
0.00110
AC:
167
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00377
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000239
AC:
60
AN:
251446
Hom.:
1
AF XY:
0.000206
AC XY:
28
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00345
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000106
AC:
155
AN:
1461120
Hom.:
0
Cov.:
30
AF XY:
0.0000908
AC XY:
66
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.00418
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.00110
AC:
167
AN:
152268
Hom.:
0
Cov.:
32
AF XY:
0.00102
AC XY:
76
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00376
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000112
Hom.:
0
Bravo
AF:
0.00126
ESP6500AA
AF:
0.00454
AC:
20
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000362
AC:
44

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ALDH1A3-related disorder Benign:1
Sep 11, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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

Isolated microphthalmia 8 Benign:1
May 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
0.021
DANN
Benign
0.97
DEOGEN2
Uncertain
0.60
.;D;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.094
N
LIST_S2
Uncertain
0.89
D;D;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.0070
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
-0.76
.;N;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.7
D;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.41
T;T;T
Sift4G
Benign
0.38
T;T;T
Polyphen
0.92
.;P;.
Vest4
0.23, 0.25
MutPred
0.52
.;Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);
MVP
0.39
MPC
1.1
ClinPred
0.094
T
GERP RS
-4.8
Varity_R
0.55
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs2229182; hg19: chr15-101425495; API