rs4646750

Positions:

• chr3-126107160-T-C

Variant summary

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

The ENST00000393434.7(ALDH1L1):​c.2434A>G​(p.Ile812Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0691 in 1,613,716 control chromosomes in the GnomAD database, including 4,282 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.079 (557 hom., cov: 34)
  • Exomes 𝑓: 0.068 (3725 hom.)
• Consequence: ALDH1L1 ENST00000393434.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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]

ALDH1L1-AS1 (HGNC:40244): (ALDH1L1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017670989).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1L1	NM_012190.4	c.2434A>G	p.Ile812Val	missense_variant	21/23	ENST00000393434.7	NP_036322.2
ALDH1L1-AS1	NR_046602.1	n.252-724T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.2434A>G	p.Ile812Val	missense_variant	21/23	1	NM_012190.4	ENSP00000377083	P1
ALDH1L1-AS1	ENST00000512384.1	n.252-724T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11943 AN: 152070 Hom.: 552 Cov.: 34

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0615

Gnomad ASJ AF: 0.0716

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0794

GnomAD3 exomes AF: 0.0589 AC: 14798 AN: 251444 Hom.: 557 AF XY: 0.0576 AC XY: 7832 AN XY: 135890

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.0660

Gnomad EAS exome AF: 0.0157

Gnomad SAS exome AF: 0.0320

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0681 AC: 99603 AN: 1461528 Hom.: 3725 Cov.: 30 AF XY: 0.0669 AC XY: 48641 AN XY: 727074

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0397

Gnomad4 ASJ exome AF: 0.0680

Gnomad4 EAS exome AF: 0.0310

Gnomad4 SAS exome AF: 0.0310

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0730

Gnomad4 OTH exome AF: 0.0702

GnomAD4 genome AF: 0.0786 AC: 11965 AN: 152188 Hom.: 557 Cov.: 34 AF XY: 0.0765 AC XY: 5695 AN XY: 74426

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0614

Gnomad4 ASJ AF: 0.0716

Gnomad4 EAS AF: 0.0214

Gnomad4 SAS AF: 0.0339

Gnomad4 FIN AF: 0.0447

Gnomad4 NFE AF: 0.0712

Gnomad4 OTH AF: 0.0852

Alfa AF: 0.0725 Hom.: 1055

Bravo AF: 0.0811

TwinsUK AF: 0.0742 AC: 275

ALSPAC AF: 0.0729 AC: 281

ESP6500AA AF: 0.116 AC: 510

ESP6500EA AF: 0.0758 AC: 652

ExAC AF: 0.0611 AC: 7423

Asia WGS AF: 0.0430 AC: 149 AN: 3478

EpiCase AF: 0.0760

EpiControl AF: 0.0772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.12	.;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T;.;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.015	.;N;.;N
MutationTaster	Benign	0.0038	P;P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.51	N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.039	.;B;.;B
Vest4		0.052
MPC		0.15
ClinPred		0.0063	T
GERP RS		2.8
Varity_R		0.067
gMVP		0.35

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: rs4646750; hg19: chr3-125826003; COSMIC: COSV56418368;