chr3-126146923-C-A

Variant names:

• chr3-126146923-C-A
• rs2886059
• NM_012190.4:c.988G>T

Variant summary

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

The NM_012190.4(ALDH1L1):​c.988G>T​(p.Val330Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,612,746 control chromosomes in the GnomAD database, including 25,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (4275 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21354 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210

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=0.012716591).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1L1	NM_012190.4	c.988G>T	p.Val330Phe	missense_variant	Exon 9 of 23	ENST00000393434.7	NP_036322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.988G>T	p.Val330Phe	missense_variant	Exon 9 of 23	1	NM_012190.4	ENSP00000377083.3

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32934 AN: 151998 Hom.: 4265 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.159 AC: 39687 AN: 249486 Hom.: 3669 AF XY: 0.154 AC XY: 20796 AN XY: 134800

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.0977

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.165 AC: 240835 AN: 1460628 Hom.: 21354 Cov.: 32 AF XY: 0.162 AC XY: 117647 AN XY: 726506

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.0958

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.217 AC: 32973 AN: 152118 Hom.: 4275 Cov.: 32 AF XY: 0.212 AC XY: 15797 AN XY: 74356

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.226

Alfa AF: 0.173 Hom.: 5253

Bravo AF: 0.227

TwinsUK AF: 0.160 AC: 592

ALSPAC AF: 0.157 AC: 607

ESP6500AA AF: 0.360 AC: 1587

ESP6500EA AF: 0.164 AC: 1412

ExAC AF: 0.165 AC: 19987

Asia WGS AF: 0.182 AC: 631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;.;T;.;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.23	T;T;.;T;T;.
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;.;L;.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	.;D;D;N;D;D
REVEL	Benign	0.033
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		0.25	.;.;B;.;B;.
Vest4		0.39
MPC		0.26
ClinPred		0.058	T
GERP RS		0.56
Varity_R		0.39
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs2886059; hg19: chr3-125865766; COSMIC: COSV56417895; COSMIC: COSV56417895;