rs2276724

chr3-126135566-T-C

Variant summary

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

The NM_012190.4(ALDH1L1):c.1441A>G(p.Ser481Gly) variant causes a missense change. The variant allele was found at a frequency of 0.157 in 1,603,936 control chromosomes in the GnomAD database, including 20,493 homozygotes. In-silico tool predicts 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 0.15 (1720 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18773 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78

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=0.0016214848).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1L1	NM_012190.4	c.1441A>G	p.Ser481Gly	missense_variant	12/23	ENST00000393434.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.1441A>G	p.Ser481Gly	missense_variant	12/23	1	NM_012190.4	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22587 AN: 152068 Hom.: 1716 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.142 AC: 33692 AN: 237286 Hom.: 2572 AF XY: 0.141 AC XY: 18191 AN XY: 128616

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.220

Gnomad SAS exome AF: 0.0826

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.157 AC: 228542 AN: 1451750 Hom.: 18773 Cov.: 33 AF XY: 0.155 AC XY: 112067 AN XY: 721882

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0994

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.0810

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.148 AC: 22599 AN: 152186 Hom.: 1720 Cov.: 32 AF XY: 0.147 AC XY: 10945 AN XY: 74412

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.219

Gnomad4 SAS AF: 0.0912

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.169

Alfa AF: 0.159 Hom.: 4610

Bravo AF: 0.149

TwinsUK AF: 0.157 AC: 584

ALSPAC AF: 0.157 AC: 606

ESP6500AA AF: 0.130 AC: 574

ESP6500EA AF: 0.163 AC: 1404

ExAC AF: 0.142 AC: 17200

Asia WGS AF: 0.152 AC: 526 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.045
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T;T;.;T;T;.
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L;.;L;L
MutationTaster	Benign	0.32	P;P;P;P;P
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.036	D;D;D;T;D;D
Polyphen		0.28	.;.;B;.;B;.
Vest4		0.28
MPC		0.21
ClinPred		0.038	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.29
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2276724; hg19: chr3-125854409; COSMIC: COSV56413444;