dbSNP rs1266949739: ALDH1L1:p.Arg531Leu (chr3-126131415-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012190.4(ALDH1L1):c.1592G>T(p.Arg531Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R531H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALDH1L1
NM_012190.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.78

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1L1	NM_012190.4	MANE Select	c.1592G>T	p.Arg531Leu	missense	Exon 13 of 23	NP_036322.2
ALDH1L1	NM_001270364.2		c.1622G>T	p.Arg541Leu	missense	Exon 13 of 23	NP_001257293.1	O75891-3
ALDH1L1	NM_001270365.2		c.1289G>T	p.Arg430Leu	missense	Exon 11 of 21	NP_001257294.1	O75891-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH1L1	ENST00000393434.7	TSL:1 MANE Select	c.1592G>T	p.Arg531Leu	missense	Exon 13 of 23	ENSP00000377083.3	O75891-1
ALDH1L1	ENST00000273450.7	TSL:1	c.1622G>T	p.Arg541Leu	missense	Exon 13 of 23	ENSP00000273450.3	O75891-3
ALDH1L1	ENST00000393431.6	TSL:1	c.1473-1122G>T		intron	N/A	ENSP00000377081.2	O75891-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456598

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107814

Other (OTH)

AF:

0.00

AC:

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.017

MutationAssessor

Pathogenic

2.9

PhyloP100

5.8

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.80

Loss of catalytic residue at R531 (P = 0.0053)

MVP

0.81

MPC

0.56

ClinPred

1.0

GERP RS

1.2

Varity_R

0.89

gMVP

0.90

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over