rs3796191

Positions:

• chr3-126153541-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012190.4(ALDH1L1):​c.761T>C​(p.Leu254Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,614,118 control chromosomes in the GnomAD database, including 2,344 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.058 (311 hom., cov: 33)
  • Exomes 𝑓: 0.048 (2033 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048755407).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1L1	NM_012190.4	c.761T>C	p.Leu254Pro	missense_variant	7/23	ENST00000393434.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.761T>C	p.Leu254Pro	missense_variant	7/23	1	NM_012190.4	P1

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8744 AN: 152158 Hom.: 306 Cov.: 33

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.0777

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0522

GnomAD3 exomes AF: 0.0579 AC: 14541 AN: 251258 Hom.: 606 AF XY: 0.0539 AC XY: 7316 AN XY: 135784

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.0171

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0759

Gnomad NFE exome AF: 0.0438

Gnomad OTH exome AF: 0.0576

GnomAD4 exome AF: 0.0475 AC: 69457 AN: 1461842 Hom.: 2033 Cov.: 31 AF XY: 0.0469 AC XY: 34078 AN XY: 727234

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.0286

Gnomad4 SAS exome AF: 0.0475

Gnomad4 FIN exome AF: 0.0752

Gnomad4 NFE exome AF: 0.0439

Gnomad4 OTH exome AF: 0.0441

GnomAD4 genome AF: 0.0576 AC: 8766 AN: 152276 Hom.: 311 Cov.: 33 AF XY: 0.0591 AC XY: 4398 AN XY: 74452

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.0977

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.0183

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.0777

Gnomad4 NFE AF: 0.0463

Gnomad4 OTH AF: 0.0516

Alfa AF: 0.0446 Hom.: 470

Bravo AF: 0.0592

TwinsUK AF: 0.0450 AC: 167

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.0690 AC: 304

ESP6500EA AF: 0.0445 AC: 383

ExAC AF: 0.0553 AC: 6719

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0412

EpiControl AF: 0.0389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.041	.;.;T;.;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.68	T;T;.;T;T;.
MetaRNN	Benign	0.0049	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;.;N;.;N;N
MutationTaster	Benign	0.00012	P;P;P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.28	.;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.39	.;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;B;.
Vest4		0.10
MPC		0.60
ClinPred		0.011	T
GERP RS		2.4
Varity_R		0.46
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs3796191; hg19: chr3-125872384;