NM_012190.4:c.1990A>G

Variant names:

• chr3-126114649-T-C
• rs749534619
• NM_012190.4:c.1990A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012190.4(ALDH1L1):​c.1990A>G​(p.Ile664Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,524,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.882
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046030432).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1L1	NM_012190.4	MANE Select	c.1990A>G	p.Ile664Val	missense	Exon 18 of 23	NP_036322.2
	ALDH1L1	NM_001270364.2		c.2020A>G	p.Ile674Val	missense	Exon 18 of 23	NP_001257293.1	O75891-3
	ALDH1L1	NM_001270365.2		c.1687A>G	p.Ile563Val	missense	Exon 16 of 21	NP_001257294.1	O75891-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1L1	ENST00000393434.7	TSL:1 MANE Select	c.1990A>G	p.Ile664Val	missense	Exon 18 of 23	ENSP00000377083.3	O75891-1
	ALDH1L1	ENST00000273450.7	TSL:1	c.2020A>G	p.Ile674Val	missense	Exon 18 of 23	ENSP00000273450.3	O75891-3
	ALDH1L1	ENST00000393431.6	TSL:1	c.*314-1769A>G		intron	N/A	ENSP00000377081.2	O75891-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000326 AC: 6 AN: 184172 AF XY: 0.0000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000245

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1372612 Hom.: 0 Cov.: 30 AF XY: 0.00000743 AC XY: 5 AN XY: 672894

African (AFR) AF: 0.0000327 AC: 1 AN: 30624

American (AMR) AF: 0.00 AC: 0 AN: 30918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20288

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38810

South Asian (SAS) AF: 0.0000139 AC: 1 AN: 71724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000936 AC: 10 AN: 1068268

Other (OTH) AF: 0.00 AC: 0 AN: 56466

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.7
DANN	Benign	0.51
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.88
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.022
Sift	Benign	0.31	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.34		Loss of methylation at K669 (P = 0.1099)
MVP		0.072
MPC		0.15
ClinPred		0.020	T
GERP RS		-1.5
Varity_R		0.024
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749534619; hg19: chr3-125833492; COSMIC: COSV56410676; COSMIC: COSV56410676;