Genetic Variant NM_000693.4:c.1156A>G (chr15-100905610-A-G) – ACMG Classification: Benign (-19 pts)

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

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 links:

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

ALDH1A3-AS1 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=0.0027904809).

BP6

Variant 15-100905610-A-G is Benign according to our data. Variant chr15-100905610-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1A3	NM_000693.4	MANE Select	c.1156A>G	p.Met386Val	missense	Exon 10 of 13	NP_000684.2	P47895
ALDH1A3	NM_001293815.2		c.835A>G	p.Met279Val	missense	Exon 7 of 10	NP_001280744.1	H0Y2X5
ALDH1A3-AS1	NR_135827.1		n.481-9544T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.1156A>G	p.Met386Val	missense	Exon 10 of 13	ENSP00000332256.5	P47895
ALDH1A3	ENST00000346623.6	TSL:1	c.835A>G	p.Met279Val	missense	Exon 7 of 10	ENSP00000343294.6	H0Y2X5
ALDH1A3	ENST00000856095.1		c.1255A>G	p.Met419Val	missense	Exon 11 of 14	ENSP00000526154.1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16010

AN:

152092

Hom.:

1755

Cov.:

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.:

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

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

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.:

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:

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

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

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:

ALSPAC

AF:

0.0226

AC:

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Isolated microphthalmia 8 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.21

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.18

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

PhyloP100

-0.16

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.39

REVEL

Benign

0.19

Sift

Benign

0.51

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.042

MPC

0.56

ClinPred

0.0010

GERP RS

-1.3

Varity_R

0.12

gMVP

0.46

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over