Genetic Variant NM_012190.4:c.2378A>G (chr3-126107216-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012190.4(ALDH1L1):c.2378A>G(p.Asp793Gly) variant causes a missense change. The variant allele was found at a frequency of 0.202 in 1,613,530 control chromosomes in the GnomAD database, including 33,783 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3102 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30681 hom. )

Consequence

ALDH1L1
NM_012190.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

Publications

48 publications found

Variant links:

Genes affected

ALDH1L1 (HGNC:3978): (aldehyde dehydrogenase 1 family member L1) The protein encoded by this gene catalyzes the conversion of 10-formyltetrahydrofolate, nicotinamide adenine dinucleotide phosphate (NADP+), and water to tetrahydrofolate, NADPH, and carbon dioxide. The encoded protein belongs to the aldehyde dehydrogenase family. Loss of function or expression of this gene is associated with decreased apoptosis, increased cell motility, and cancer progression. There is an antisense transcript that overlaps on the opposite strand with this gene locus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ALDH1L1 links:

ALDH1L1-AS1 (HGNC:40244): (ALDH1L1 antisense RNA 1)

ALDH1L1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026737452).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1L1	NM_012190.4 link	c.2378A>G	p.Asp793Gly	missense_variant	Exon 21 of 23	ENST00000393434.7	NP_036322.2	O75891-1Q53H87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1L1	ENST00000393434.7 link	c.2378A>G	p.Asp793Gly	missense_variant	Exon 21 of 23	1	NM_012190.4	ENSP00000377083.3		O75891-1

Frequencies

GnomAD3 genomes

AF:

0.198

AC:

30131

AN:

152116

Hom.:

3099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.185

AC:

46395

AN:

251432

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.202

AC:

295779

AN:

1461296

Hom.:

30681

Cov.:

AF XY:

0.204

AC XY:

148333

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.220

AC:

7376

AN:

33466

American (AMR)

AF:

0.120

AC:

5364

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

6775

AN:

26136

East Asian (EAS)

AF:

0.130

AC:

5180

AN:

39698

South Asian (SAS)

AF:

0.226

AC:

19532

AN:

86242

European-Finnish (FIN)

AF:

0.127

AC:

6796

AN:

53366

Middle Eastern (MID)

AF:

0.247

AC:

1425

AN:

5768

European-Non Finnish (NFE)

AF:

0.207

AC:

230564

AN:

1111540

Other (OTH)

AF:

0.212

AC:

12767

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

11857

23714

35572

47429

59286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8020

16040

24060

32080

40100

<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:

0.198

AC:

30142

AN:

152234

Hom.:

3102

Cov.:

AF XY:

0.194

AC XY:

14412

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.220

AC:

9156

AN:

41536

American (AMR)

AF:

0.169

AC:

2585

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

914

AN:

3468

East Asian (EAS)

AF:

0.129

AC:

669

AN:

5170

South Asian (SAS)

AF:

0.229

AC:

1105

AN:

4820

European-Finnish (FIN)

AF:

0.123

AC:

1303

AN:

10618

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13702

AN:

68006

Other (OTH)

AF:

0.232

AC:

490

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1297

2594

3892

5189

6486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.206

Hom.:

14616

Bravo

AF:

0.202

TwinsUK

AF:

0.201

AC:

746

ALSPAC

AF:

0.199

AC:

767

ESP6500AA

AF:

0.213

AC:

940

ESP6500EA

AF:

0.216

AC:

1855

ExAC

AF:

0.189

AC:

22887

Asia WGS

AF:

0.210

AC:

729

AN:

3478

EpiCase

AF:

0.218

EpiControl

AF:

0.222

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

.;T;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.68

T;.;T;T

MetaRNN

Benign

0.0027

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;L

PhyloP100

4.0

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Benign

0.15

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.0030

.;B;.;B

Vest4

0.14

MPC

0.25

ClinPred

0.019

GERP RS

4.0

Varity_R

0.30

gMVP

0.80

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

Other links and lift over