3-126125636-C-G

Variant names:

• chr3-126125636-C-G
• rs778022672
• NM_012190.4:c.1780G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012190.4(ALDH1L1):​c.1780G>C​(p.Val594Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,443,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. V594M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.878
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23776826).

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.1780G>C	p.Val594Leu	missense	Exon 15 of 23	NP_036322.2
	ALDH1L1	NM_001270364.2		c.1810G>C	p.Val604Leu	missense	Exon 15 of 23	NP_001257293.1	O75891-3
	ALDH1L1	NM_001270365.2		c.1477G>C	p.Val493Leu	missense	Exon 13 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.1780G>C	p.Val594Leu	missense	Exon 15 of 23	ENSP00000377083.3	O75891-1
	ALDH1L1	ENST00000273450.7	TSL:1	c.1810G>C	p.Val604Leu	missense	Exon 15 of 23	ENSP00000273450.3	O75891-3
	ALDH1L1	ENST00000393431.6	TSL:1	c.*111G>C		3_prime_UTR	Exon 14 of 21	ENSP00000377081.2	O75891-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000835 AC: 2 AN: 239388 AF XY: 0.00000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1443800 Hom.: 0 Cov.: 30 AF XY: 0.00000557 AC XY: 4 AN XY: 717612

African (AFR) AF: 0.00 AC: 0 AN: 32878

American (AMR) AF: 0.00 AC: 0 AN: 43128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38402

South Asian (SAS) AF: 0.00 AC: 0 AN: 83210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102346

Other (OTH) AF: 0.0000168 AC: 1 AN: 59588

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.88
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.092
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.0050	B
Vest4		0.37
MutPred		0.70		Loss of glycosylation at T593 (P = 0.0196)
MVP		0.13
MPC		0.18
ClinPred		0.087	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.81
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs778022672; hg19: chr3-125844479;